Dependencies of CYLD

HGNC Gene Name: CYLD lysine 63 deubiquitinase
HGNC Gene Symbol: CYLD
Identifiers: hgnc:2584 ncbigene:1540 uniprot:Q9NQC7
Orthologs: mgi:1921506 rgd:1308346
NDEx Network: 2d4f056b-caca-11eb-9a85-0ac135e8bacf
INDRA Statements: deubiquitinations all statements
Pathway Commons: Search for CYLD
Number of Papers: 635

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis. The dependency score quantifies the rate of CRISPR-Cas9 guide drop out for each guide in each cell line. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes for DUBs and ran GO enrichment analysis in order to explore the pathways and complexes DUBs are correlated with in the DepMap. We sought to provide support for the co-dependent genes being in the same pathway or complex by leveraging additional datasets. We used BioGRID, IntAct, and Pathway Commons PPIDs, and the NURSA PPID to determine whether co-dependent genes interact with one another. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap).

DepMap Correlations

Symbol	Name	DepMap Correlation	Evidence	CCLE Correlation	CCLE Z-score	CCLE p-value (adj)	CMAP Score	CMAP Type
N4BP1	NEDD4 binding protein 1	0.466		0.32	1.69	1.40e-07
TRAF3	TNF receptor associated factor 3	0.383	INDRA	0.11	0.53	1.36e-01	99.44	kd
NFKBIA	NFKB inhibitor alpha	0.283	INDRA	0.14	0.66	1.22e-01	90.25	oe
TNFAIP3	TNF alpha induced protein 3	0.272	INDRA	0.14	0.66	7.05e-02	-94.74	oe
TRAF2	TNF receptor associated factor 2	0.242	BioGRID Pathway Commons INDRA	0.25	1.30	6.91e-05	99.91	oe
BCL10	BCL10 immune signaling adaptor	-0.233		0.24	1.21	2.22e-04	99.95	oe
CHUK	component of inhibitor of nuclear factor kappa B kinase complex	-0.231		0.27	1.38	2.23e-05

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with CYLDusing the terms from Gene Ontology and gene sets derived from theGene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier	GO Name	GO Type	p-value	p-value (adj.)	q-value
GO:0002224	toll-like receptor signaling pathway	Biological Process	4.87e-10	2.23e-07	4.52e-08
GO:0051090	regulation of DNA-binding transcription factor activity	Biological Process	9.24e-10	4.23e-07	4.52e-08
GO:0033209	tumor necrosis factor-mediated signaling pathway	Biological Process	1.03e-09	4.72e-07	4.52e-08
GO:0002221	pattern recognition receptor signaling pathway	Biological Process	2.25e-09	1.03e-06	7.40e-08
GO:0035631	CD40 receptor complex	Cellular Component	5.07e-09	2.32e-06	1.33e-07
GO:0007249	I-kappaB kinase/NF-kappaB signaling	Biological Process	1.05e-08	4.81e-06	2.30e-07
GO:0032088	negative regulation of NF-kappaB transcription factor activity	Biological Process	1.57e-08	7.17e-06	2.94e-07
GO:0034612	response to tumor necrosis factor	Biological Process	2.30e-08	1.06e-05	3.65e-07
GO:0002218	activation of innate immune response	Biological Process	2.50e-08	1.14e-05	3.65e-07
GO:0045088	regulation of innate immune response	Biological Process	1.33e-07	6.07e-05	1.74e-06
GO:0043433	negative regulation of DNA-binding transcription factor activity	Biological Process	2.13e-07	9.76e-05	2.55e-06
GO:0031663	lipopolysaccharide-mediated signaling pathway	Biological Process	8.92e-07	4.09e-04	9.78e-06
GO:0010803	regulation of tumor necrosis factor-mediated signaling pathway	Biological Process	1.10e-06	5.02e-04	1.11e-05
GO:0070646	protein modification by small protein removal	Biological Process	2.04e-06	9.33e-04	1.92e-05
GO:0044389	ubiquitin-like protein ligase binding	Molecular Function	2.23e-06	1.02e-03	1.96e-05
GO:0002237	response to molecule of bacterial origin	Biological Process	3.44e-06	1.57e-03	2.83e-05
GO:0031996	thioesterase binding	Molecular Function	6.41e-06	2.93e-03	4.96e-05
GO:0070431	nucleotide-binding oligomerization domain containing 2 signaling pathway	Biological Process	9.08e-06	4.16e-03	6.64e-05
GO:0032606	type I interferon production	Biological Process	9.82e-06	4.50e-03	6.80e-05
GO:0002697	regulation of immune effector process	Biological Process	1.08e-05	4.94e-03	7.10e-05
GO:0051092	positive regulation of NF-kappaB transcription factor activity	Biological Process	1.69e-05	7.74e-03	1.06e-04
GO:0007252	I-kappaB phosphorylation	Biological Process	1.78e-05	8.15e-03	1.06e-04
GO:2001236	regulation of extrinsic apoptotic signaling pathway	Biological Process	1.86e-05	8.53e-03	1.07e-04
GO:0032495	response to muramyl dipeptide	Biological Process	2.21e-05	1.01e-02	1.21e-04
GO:0034614	cellular response to reactive oxygen species	Biological Process	2.33e-05	1.06e-02	1.22e-04
GO:0098562	cytoplasmic side of membrane	Cellular Component	2.58e-05	1.18e-02	1.28e-04
GO:0060759	regulation of response to cytokine stimulus	Biological Process	2.67e-05	1.22e-02	1.28e-04
GO:0038061	NIK/NF-kappaB signaling	Biological Process	2.72e-05	1.24e-02	1.28e-04
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB signaling	Biological Process	2.95e-05	1.35e-02	1.34e-04
GO:0051059	NF-kappaB binding	Molecular Function	4.71e-05	2.16e-02	2.00e-04
GO:0097191	extrinsic apoptotic signaling pathway	Biological Process	5.49e-05	2.51e-02	2.06e-04
GO:0005164	tumor necrosis factor receptor binding	Molecular Function	5.40e-05	2.47e-02	2.06e-04
GO:0001782	B cell homeostasis	Biological Process	5.05e-05	2.31e-02	2.06e-04
GO:1903320	regulation of protein modification by small protein conjugation or removal	Biological Process	5.27e-05	2.41e-02	2.06e-04
GO:0002756	MyD88-independent toll-like receptor signaling pathway	Biological Process	5.76e-05	2.64e-02	2.10e-04
GO:0000302	response to reactive oxygen species	Biological Process	6.01e-05	2.75e-02	2.14e-04
GO:0071216	cellular response to biotic stimulus	Biological Process	6.17e-05	2.83e-02	2.14e-04
GO:0034142	toll-like receptor 4 signaling pathway	Biological Process	6.51e-05	2.98e-02	2.20e-04
GO:0035872	nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	Biological Process	7.31e-05	3.35e-02	2.40e-04
GO:1902042	negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	Biological Process	7.72e-05	3.54e-02	2.48e-04
GO:0051091	positive regulation of DNA-binding transcription factor activity	Biological Process	8.84e-05	4.05e-02	2.77e-04

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking down CYLD.

Knockdown Differential Expression

Symbol	Name	log₂-fold-change	p-value	p-value (adj.)
BIRC3	baculoviral IAP repeat containing 3	1.01e+00	1.57e-18	1.99e-14
CXCL8	C-X-C motif chemokine ligand 8	1.49e+00	3.06e-17	1.94e-13
CSF2	colony stimulating factor 2	1.20e+00	5.02e-16	2.12e-12
CXCL2	C-X-C motif chemokine ligand 2	1.27e+00	5.83e-10	1.73e-06
CXCL3	C-X-C motif chemokine ligand 3	1.34e+00	7.57e-10	1.73e-06
LAMC2	laminin subunit gamma 2	9.68e-01	8.20e-10	1.73e-06
SOD2	superoxide dismutase 2	6.95e-01	1.04e-09	1.88e-06
G0S2	G0/G1 switch 2	4.73e-01	1.74e-09	2.76e-06
CXCL1	C-X-C motif chemokine ligand 1	1.10e+00	2.19e-09	3.08e-06
MMP1	matrix metallopeptidase 1	4.45e-01	4.90e-09	6.20e-06
IL1B	interleukin 1 beta	1.34e+00	7.86e-09	9.04e-06
TNFSF15	TNF superfamily member 15	9.28e-01	9.39e-09	9.90e-06
C15orf48	chromosome 15 open reading frame 48	7.19e-01	1.07e-08	1.04e-05
ICAM1	intercellular adhesion molecule 1	1.00e+00	4.30e-08	3.89e-05
NAMPT	nicotinamide phosphoribosyltransferase	5.70e-01	4.62e-08	3.90e-05
TFPI2	tissue factor pathway inhibitor 2	7.05e-01	6.85e-08	5.42e-05
CSF3	colony stimulating factor 3	1.29e+00	1.41e-07	1.05e-04
PTX3	pentraxin 3	6.63e-01	2.45e-07	1.73e-04
SYNGR2	synaptogyrin 2	6.75e-01	7.33e-07	4.88e-04
NFKBIA	NFKB inhibitor alpha	5.70e-01	3.07e-06	1.94e-03
KYNU	kynureninase	7.62e-01	1.35e-05	8.13e-03
DUSP28	dual specificity phosphatase 28	9.38e-01	2.31e-05	1.33e-02
AKR1B1	aldo-keto reductase family 1 member B	3.56e-01	2.97e-05	1.63e-02
SERPIND1	serpin family D member 1	7.78e-01	4.99e-05	2.63e-02
CD44	CD44 molecule (Indian blood group)	3.75e-01	5.72e-05	2.89e-02
IL6	interleukin 6	7.86e-01	7.26e-05	3.54e-02
SAA2	serum amyloid A2	5.76e-01	1.10e-04	4.99e-02
SQSTM1	sequestosome 1	4.96e-01	1.09e-04	4.99e-02

INDRA Statements

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach

CYLD deubiquitinates TRAF2. 10 / 10

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For instance, CYLD deubiquitinates the K63-Ub chains of TRAF2 and, to some extent, TRAF6, and inhibits NF-kappaB activity.

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Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract)

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Using an shRNA approach, Brummelkamp et al. showed that CYLD inhibits NF-kappaB signaling by counteracting TRAF2 ubiquitination [XREF_BIBR].

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The steady state association of TRAF2 with MLKL was diminished upon TNF induced necroptosis induction, and this correlated with CYLD dependent deubiquitylation of TRAF2.

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CYLD, a protease that specifically cleaves K63-ubiquitin chains, de-ubiquitinates TRAF2, thereby inhibiting the recruitment of TAB and TAK and activation of IKK [15], and A20 deactivates RIP1 by remov[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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CYLD mediated regulation of the JNK signaling pathway appears to target TRAF2 ubiquitylation, as CYLD knockdown increases both TRAF2 ubiquitylation and JNK activation, further enhancing cell survival [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The Cylindroma tumour suppressor protein (CYLD) de-ubiquitinates NEMO and TRAF2 [XREF_BIBR - XREF_BIBR], while USP15 reverses betaTRCP mediated ubiquitination of IkappaBalpha [XREF_BIBR].

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Here we described that the adenoviral vector expressing CYLD (Ad/hTERT-CYLD) augmented the cytotoxicity of TRAIL in HCC cells by negatively regulating NF-kappaB activity since CYLD could reverse the ubiquitination of TNF receptor associated factor 2 (TRAF2) and interact with the IkappaB kinasegamma (IKKgamma).

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Another example is already mentioned CYLD, which is an important inflammatory mediator that deubiquitinates TRAF2 and TRAF6, resulting in negative regulation of the NF-kappaB pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

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To verify this hypothesis, we examined CYLDex7/8 -/- mice, which lack the full CYLD molecule but overexpress a shorter CYLD isoform (sCYLD) that is unable to bind to and thus deubiquitinate TRAF2.

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CYLD deubiquitinates TRAF6. 10 / 10

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CYLD binding to one of its targets, TRAF6, requires the adaptor protein p62, which promotes the deubiquitylation of TRAF6 by CYLD 17 and probably also modulates the DUB activity of CYLD through induction of CYLD ubiquitylation 34.

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Previously it has been known that TNF receptor associated factor 6 (TRAF6) acts as an E3 ligase for Akt-K63 polyubiquitination, and CYLD deubiquitinates TRAF6.

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CYLD also decreased IFN promotor activation by deubiquitinating TRAF2 and TRAF6 in HEK293 T cells, respectively [29, 30] .

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Then we investigated the roles A20 and CYLD in CK8 mediated inhibition of TRAF6 ubiquitination.

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Conversely, the PB1 domain of p62 also interacts with CYLD, a deubiquitinase, which inhibits TRAF6 polyubiquitination and serves as a negative regulator for RANK mediated NF-kappaB activation and osteoclastogenesis 113.

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In support of this notion, in vivo poly-ubiquitination assays demonstrate that depletion of beta-TRCP impaired TRAF6 self ubiquitination likely due to enhancement of TRAF6 deubiquitination by CYLD, concomitant with a reduction in beta-TRCP-dependent ubiquitination of CYLD and impairment of auto-phosphorylation of TRAF6-downstream kinase IKKalpha.

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Specifically, as suggested by Jin et al. [XREF_BIBR], deubiquitinating enzyme CYLD negatively regulated TRAF6 ubiquitination by interacting with P62 and subsequently inhibited proangiogenesis function of TRAF6.

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Here we demonstrated that during the RANKL dependent signaling pathway, CYLD stabilization by depletion of beta-TRCP decreased the ubiquitination of TRAF6 and impaired auto-phosphorylation of the TRAF6-downstream kinase IKKalpha.

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[XREF_BIBR] CYLD deubiquitination of TRAF6, RIP1, and NF-kappaB-essential modulator (NEMO) leads to inactivation of NF-kappaB signaling.

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In the absence of any robust stimulation of NF-kappaB (such as TCR engagement or cytokine signaling), CYLD deubiquitylates TRAF2, TRAF6, and NEMO, dampening NF-kappaB signaling by removing activating K63 chains formed by TRAF2/6.

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CYLD deubiquitinates RIPK1. 10 / 10

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Another possibility is that in cells lacking normal Optn, some other protein may act as an adaptor to facilitate CYLD dependent deubiquitination of RIP.

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Deubiquitination of RIP by over-expressed CYLD was abrogated in optineurin knockdown cells.

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32 Last but not least, CYLD interacts with and deubiquitinates RIP1.

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This process starts with the accelerated degradation of cIAP1/2 induced by Smac protein (or Smac mimetics), and proceeds with release of RIPK1 from the TNFRI, deubiquitination of RIPK1 by the deubiqui[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Conversely, deubiquitination of RIP1 by CYLD or the absence of cIAPs and LUBAC renders complex I unstable and facilitates other complexes assembled to initiate apoptosis or necroptosis.

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Then, a tumor suppressor cylindromatosis (CYLD) protein promotes the deubiquitination of RIP1 in either complex I or complex II.

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It does this by binding to ubiquitinated RIP (receptor interacting protein) to displace IKBKG (inhibitor of kappaB kinase gamma), and then bringing in cylindromatosis (CYLD) to deubiquitinate RIP and terminate the signaling pathway XREF_BIBR - XREF_BIBR.

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Thus, apoptosis and necrosis induced by death inducing cytokines share a common biochemical pathway down to the step of RIPK1 activation following receptor activation, cIAP1/2 degradation, and deubiqu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Deubiquitination of RIPK1 by CYLD 81 stimulates the dissociation of Complex I into a secondary cytoplasmic Complex IIa where RIPK1 and/or TRADD recruit FADD via their DDs.

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CYLD can deubiquitinate RIPK1, freeing it to be phosphorylated and complex with RIPK3 (Complex IIb) to form the necrosome [XREF_BIBR - XREF_BIBR].

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CYLD deubiquitinates BCL3. 10 / 10

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In these cases, mutated CYLD is unable to deubiquitinate Bcl-3, allowing increased proliferation in cell of the skin adnexa [XREF_BIBR].

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The CYLD protein deubiquitinates Bcl-3 and inhibits its nuclear translocation, so alterations in these gene or upstream events to it present an additional layer of regulation.

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CYLD is also able to deubiquitinate Bcl-3 and prevent it from entering nucleus, where Bcl-3 can interact with NFkappaB family members (p50 and p52) to activate the transcription of NFkappaB target genes.

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In addition to its deubiquitination effects on TRAFs and IKKgamma, CYLD also deubiquitinates Bcl-3, and in so doing prevents its nuclear localization.

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CYLD deubiquitinates several NF-kappaB regulators, including TRAF2, TRAF6, and NEMO as well as BCL3, a member of the NF-kappaB family of transcription factors.

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In this issue of Cell, Massoumi et al. (2006) show that CYLD deubiquitinates the coactivator Bcl-3, thereby preventing its translocation into the nucleus, where it normally interacts with NF-kappaB and activates transcription of proliferation genes in response to growth signals.

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In our experiments, the inhibitory effect of CYLD on the nuclear accumulation of phosphorylated STAT3 resembles CYLD-Bcl3 interaction, since CYLD also deubiquitinates Bcl-3 in perinuclear regions and prevents its translocation to the nucleus, a process which significantly contributes to the development of keratinocyte hyperproliferation and development of benign tumors of the skin appendage called cylindromatosis XREF_BIBR.

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CYLD deubiquitylates BCL-3 inhibiting its nuclear translocation and so decreases the transcription of BCL-3 target genes including CCND [XREF_BIBR].

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In the present study, the cytoplasmic and perinuclear expression levels of CYLD suggest that CYLD may play a role in the deubiquitination of BCl-3 and/or TRAF in NF-kappaB signaling within the cytoplasm or perinuclear region in keratinocytes of normal skin and cholesteatoma, in agreement with previously reported results.

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Cyld binds and deubiquitinates bcl-3in cyld+/+ keratinocytes, tpa or uv light triggers the translocation of cyld from the cytoplasm to the perinuclear region, where cyld binds and deubiquitinates bcl-3, thereby preventing nuclear accumulation of bcl-3 and p50/bcl-3- or p52/bcl-3-dependent proliferation.

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CYLD deubiquitinates IKBKG. 9 / 9

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To confirm that Tax- or TRAF6 induced polyubiquitination of NEMO is blocked by CYLD expression, NEMO and an HA tagged ubiquitin mutant (HA-K63Ub) were co-expressed with Tax or TRAF6 in the presence or[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The Cylindroma tumour suppressor protein (CYLD) de-ubiquitinates NEMO and TRAF2 [XREF_BIBR - XREF_BIBR], while USP15 reverses betaTRCP mediated ubiquitination of IkappaBalpha [XREF_BIBR].

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CYLD also deubiquitinates IkappaB kinase gamma (IKKgamma, also known as NEMO), the regulatory subunit of IKK thus inhibiting the activation of IKK.

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When transfected into mammalian cells, CYLD deubiquitinates NEMO as well as several IKK upstream regulators, including TRAF2, TRAF6, TRAF7, RIP1, and Tak1.

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CYLD physically interacts with and deubiquitinates NEMO, thereby negatively regulating NF-kappaB activation [XREF_BIBR].

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CYLD deubiquitinates NEMO, thus decreasing its stability and preventing the IKK complex from phosphorylating IkappaB, and NF-kappaB activation.

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Deubiquitinating enzyme CYLD inhibits NEMO linear ubiquitination, possibly by disassembling both K63 linked and linear polyubiquitin.

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CYLD can deubiquitinate NEMO, preventing it from causing phosphorylation of IkB, thereby killing the signal [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

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CYLD deubiquitinates TP53. 8 / 8

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As shown in XREF_FIG and XREF_SUPPLEMENTARY, in contrast to WT CYLD, the catalytically inactive CYLDR936X (R/X) and CYLDH871N (H/N) mutants did not diminish p53 ubiquitination although they bound p53, demonstrating that CYLD DUB activity is required to reduce p53 ubiquitination.

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To address this question, we first assessed the capacity of CYLD to reduce p53 ubiquitination in cells overexpressing HA tagged Lys-to-Arg ubiquitin mutants that can only form K48- or K63 linked chains.

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Together, these results suggested that CYLD directly interacts with and deubiquitinates p53 facilitating its optimal stabilization in response to DNA damage.

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Mechanistically, we show that CYLD interacts with and deubiquitinates p53 in response to DNA damage.

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Furthermore, recombinant His CYLD reduced ubiquitination of Flag-p53 immunoprecipitated from CpT treated HEK293T cells, showing that CYLD can directly deubiquitinate p53 in a cell-free in vitro assay (XREF_SUPPLEMENTARY).

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CYLD deubiquitinates p53 facilitating its stabilization.

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This experiment showed that CYLD diminishes p53 ubiquitination in cells expressing HA-mutant ubiquitin forming K63 only chains, but also in cells expressing HA-mutant ubiquitin forming K48 only chains (XREF_FIG).

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Mechanistically, CYLD interacts with and deubiquitinates p53 facilitating its stabilization in response to genotoxic stress.

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CYLD deubiquitinates MAP3K7. 8 / 8

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CYLD does not inhibit TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination.

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Indeed, our data suggest that CYLD directly targets Tak1 and inhibits Tak1 ubiquitination.

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Although it is not yet clear precisely how CYLD regulates the function of the CARMA1-BCL-10-MALT1 signalosome, CYLD deubiquitylates TAK1 and thereby suppresses its catalytic activity 19.

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These results indicate that USP4 mainly inhibits inducible TAK1 polyubiquitination and activation whereas CYLD mainly inhibits basal level of TAK1 polyubiquitination and activation.

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Finally, we showed that CYLD interacts with and deubiquitinates TAK1 to negatively regulate the activation of the downstream MKK3/6-p 38alpha/beta pathway.

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In this investigation, we found that CYLD failed to inhibit TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappaB activation (XREF_FIG, XREF_SUPPLEMENTARY).

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Koga et al. had reported that CYLD interacted with and deubiquitinates TAK1 by negatively regulating the activation of the downstream MKK3/6-p 38alpha/beta pathway to resist the infection of gram positive bacterium Streptococcus pneumonia [XREF_BIBR].

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Inclusion of Cyld (WT) (XREF_FIG, lane3) but not Cyld (C601A) mutant (XREF_FIG, lane4) that lacks the DUB activity 37 resulted in diminished Tak1 ubiquitination suggesting that Cyld deubiquitinated Tak1.

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CYLD deubiquitinates DDX58. 8 / 8

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CYLD can inhibit ubiquitination of the RIG1 cytoplasmic viral RNA sensor and also downregulate antiviral Interferon production by controlling IKK activation [XREF_BIBR].

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XREF_BIBR, XREF_BIBR We and others have recently shown that RIG-I ubiquitination and TBK1 and IKKepsilon activation are negatively regulated by CYLD, XREF_BIBR, XREF_BIBR a deubiquitinase known to digest K63 linked ubiquitin chains.

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CYLD (cylindromatosis) deubiquitinates RIG-I and several downstream molecules to prevent premature RIG-I activation in uninfected cells [17], while USP3 deubiquitinates RIG-I specifically after viral infection, likely serving as a negative feedback regulator [18].

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ORF64, USP25, USP21, USP15, USP3, Cylindromatosis (CYLD), porcine epidemic diarrhea virus papain-like protease 2 (PEDV PLP2) and transmissible gastroenteritis virus papain-like protease1 (TGEV PL1) are the DUBs found to deubiquitinate RIG-I.

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CYLD has been shown to deubiquitinate, or prevent ubiquitination of RIG-I in cells.

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CYLD (cylindromatosis) deubiquitinates RIG-I and several downstream molecules to prevent premature RIG-I activation in uninfected cells [XREF_BIBR], while USP3 deubiquitinates RIG-I specifically after viral infection, likely serving as a negative feedback regulator [XREF_BIBR].

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Tumor suppressor protein cylindromatosis (CYLD) reduced the baseline Lys63-linked ubiquitination of RIG-I in uninfected cells [69].

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A simple explanation for this result is that the carboxyl-terminal fragment of SDC4 brings RIG-I and CYLD close together, which promotes the deubiquitination of RIG-I by CYLD.

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CYLD deubiquitinates AKT. 8 / 8

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To determine whether CYLD is a direct DUB for Akt, we performed in vitro deubiquitination assays and found that deubiquitination of Akt was mediated by wild-type CYLD but not the C601A mutant (XREF_FIG).

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Because CYLD is a known deubiquitinase and Akt ubiquitination is critical for its functional activity XREF_BIBR, we next investigated whether CYLD deubiquitinates Akt.

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In this study we provided experimental evidences for direct interaction between Akt and CYLD, and also showed that CYLD does directly deubiquitinate Akt under both endogenous and exogenous conditions.

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Among the DUBs, only CYLD effectively reduced the ubiquitination of Akt (XREF_FIG and XREF_SUPPLEMENTARY).

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Both E3 ligases TRAF6 [158] and Skp2 [159] regulate Akt activity through K63 linked ubiquitination while CYLD promotes deubiquitination of Akt [160].

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Reversely, CYLD negatively regulates Akt signaling by deubiquitinating Akt in TGFbeta signaling [XREF_BIBR].

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Because CYLD suppresses ubiquitination and activation of Akt, it is possible that CYLD may also inhibit cancer cell proliferation and survival.

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CYLD repression by miR-130b restores Akt ubiquitination and activation, GSK3beta and FoxO3a phosphorylation, FoxO3a removal from Bim promoter as well as Bim downregulation during 6-OHDA administration.

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CYLD deubiquitinates NFkappaB. 6 / 6

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In vivo, CYLD also reduced hepatic STAT3 K63 ubiquitination and activation, NF-kappaB activation, IL-6 and NOX2 mRNA production as well as fibrin production in murine listeriosis.

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Deubiquitination of NF-kappaB members by CYLD is crucial in controlling the magnitude and nature of cell activation.

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CYLD deubiquitinates NEMO, thus decreasing its stability and preventing the IKK complex from phosphorylating IkappaB, and NF-kappaB activation.

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In this investigation, we found that CYLD failed to inhibit TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappaB activation (XREF_FIG, XREF_SUPPLEMENTARY).

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CYLD deubiquitinates several NF-kappaB regulators, including TRAF2, TRAF6, and NEMO as well as BCL3, a member of the NF-kappaB family of transcription factors.

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18 CYLD 's deubiquitination of NFkappaB inhibits NFkappaB activity without decreasing NFkappaB protein expression.

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CYLD deubiquitinates Tax. 4 / 4

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CYLD inhibits Tax ubiquitination.

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Since CYLD deubiquitinates Tax, we examined the effect of CYLD on these Tax specific signaling events.

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Since CYLD is a K63 specific DUB, we examined whether the ubiquitination of Tax is negatively regulated by CYLD.

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As expected, the wildtype CYLD, but not its catalytically inactive mutant, efficiently inhibited Tax ubiquitination.

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CYLD leads to the deubiquitination of DVL. 3 / 3

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It is also reported that a tumor suppressor CYLD deubiquitinase inhibits the ubiquitination of Dvl.

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Knockout of CYLD in tumor cells can prevent K63 linked deubiquitination of Dvl [Dishevelled], which enhances Wnt and beta-catenin signaling [XREF_BIBR].

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Based on the established role of Wnt signaling in self-renewal of the skin, associated cell lineage decisions, and skin appendage formation (Fuchs, 2007), we propose that increased or prolonged activa[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Mutated CYLD deubiquitinates Tax. 3 / 3

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Consistently, a phospho-mimetic CYLD mutant fails to inhibit Tax ubiquitination.

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A phospho-mimetic CYLD mutant failed to inhibit Tax ubiquitination.

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Importantly, a phospho-mimetic CYLD mutant harboring serine to glutamic acid substitutions at the phosphorylation sites completely failed to deubiquitinate Tax, whereas a mutant harboring serine to analine mutations at the phsphorylation sites of CYLD (CYLD7SA) remained active in Tax deubiquitination.

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CYLD leads to the deubiquitination of IKBKE. 3 / 3

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We further show that CYLD targets a cytoplasmic RNA sensor, RIG-I, and inhibits the ubiquitination of this IKKepsilon and TBK1 stimulator.

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In addition, CYLD also inhibits the ubiquitination of TBK1 and IKKepsilon, which also contributes to the negative regulation of IFN responses by CYLD 79.

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CYLD deubiquitinates IKK_complex. 3 / 3

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CYLD also deubiquitinates IkappaB kinase gamma (IKKgamma, also known as NEMO), the regulatory subunit of IKK thus inhibiting the activation of IKK.

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CYLD also inhibits the ubiquitylation of TBK1 and IKKε, which contributes to the negative regulation of IFN responses 171 .

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When transfected into mammalian cells, CYLD deubiquitinates NEMO as well as several IKK upstream regulators, including TRAF2, TRAF6, TRAF7, RIP1, and Tak1.

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CYLD leads to the deubiquitination of TBK1. 3 / 3

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In addition, CYLD also inhibits the ubiquitination of TBK1 and IKKepsilon, which also contributes to the negative regulation of IFN responses by CYLD 79.

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CYLD also inhibits the ubiquitylation of TBK1 and IKKε, which contributes to the negative regulation of IFN responses 171 .

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CYLD deubiquitinates ARHGEF12. 2 / 2

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In the present study, we show that CYLD deubiquitinates LARG, thus adding LARG to the growing list of CYLD substrates.

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Taken together, our data provide the first evidence that CYLD deubiquitinates LARG and increases its ability to catalyze the GDP/GTP exchange on RhoA.

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Modified CYLD leads to the deubiquitination of TRAF2. 2 / 2

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Indeed, immunoprecipitation analysis showed that overexpression of CYLD induced deubiquitination of TRAF2 in ECs.

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Of importance, overexpression of catalytically inactive CYLD did not induce deubiquitination of TRAF2.

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CYLD deubiquitinates MIB2. 2 / 2

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Moreover, MIB2, an E3 ligase for the Notch ligand JAG2, is deubiquitinated and stabilized by CYLD.

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As we demonstrated that MIB2 can ubiquitylate itself as well as CYLD, we postulated that CYLD, as an ubiquitin hydrolase, might deubiquitylate MIB2, hence providing a potential mechanism of mutual regulation.

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CYLD deubiquitinates IKBKG on K285. 2 / 2

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CYLD deubiquitinates NTRK1. 2 / 2

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In the internalization of the nerve growth factor receptor TrkA, siRNA mediated suppression of CYLD causes sustained TrkA ubiquitination with Lys63 chains (Geetha et al., 2005).

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Geetha and collaborators saw that the polyubiquitination of TrkA increases when CYLD is depleted, but no direct evidence of TrkA deubiquitination by CYLD was provided [XREF_BIBR].

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CYLD leads to the deubiquitination of TAB1. 1 / 1

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CYLD does not inhibit TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination.

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CYLD leads to the deubiquitination of DVL1. 1 / 1

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Ubiquitination of Dvl1 was diminished by overexpression of wild-type CYLD and enhanced by overexpression of a catalytically inactive CYLD (CYLD C601S).

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Modified CYLD leads to the deubiquitination of TRAF6. 1 / 1

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We showed that CYLD over-expression largely inhibited TRAF-6 ubiquitination, a step that is required for its activation.

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CYLD leads to the deubiquitination of JUN. 1 / 1

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CYLD suppresses AP1 function by regulating c-Jun and c-Fos ubiquitination.

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CYLD deubiquitinates DDX58 ubiquitinated on K172 and K154 on K164. 1 / 1

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USP15 deubiquitinates CYLD. 1 / 1

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UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.

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CYLD leads to the deubiquitination of MYD88. 1 / 1

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Although it is unclear whether this ubiquitination event is mediated by TRAF6 or another E3, the ubiquitination of MyD88 is negatively regulated by the DUB CYLD and is important for activating downstream proinflammatory signaling.

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CYLD deubiquitinates RIPK3. 1 / 1

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CYLD deficiency leads to hyperubiquitinated RIPK1 in the necrosome and impaired phosphorylation of RIPK1 and RIPK3, thereby blocking caspase-8 activation.

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CYLD leads to the deubiquitination of TNFRSF1A. 1 / 1

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CYLD, a deubiquitinating enzyme that targets both M1- and K63 linked ubiquitin chains, is recruited to TNF-RSC to negatively regulate ubiquitinations of RIPK1, TNFR1, NEMO and TRADD to attenuate the NF-kappaB pathway and promote both apoptosis and necroptosis.

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CYLD deubiquitinates NLRP6. 1 / 1

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Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation.

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CYLD leads to the deubiquitination of CYBB. 1 / 1

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In vivo, CYLD also reduced hepatic STAT3 K63 ubiquitination and activation, NF-kappaB activation, IL-6 and NOX2 mRNA production as well as fibrin production in murine listeriosis.

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CYLD leads to the deubiquitination of TGFB. 1 / 1

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Reversely, CYLD negatively regulates Akt signaling by deubiquitinating Akt in TGFbeta signaling [XREF_BIBR].

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CYLD leads to the deubiquitination of AKT2. 1 / 1

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CYLD deubiquitinates SMAD7 at position 374. 1 / 1

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Under endogenous conditions, CYLD formed a complex with Smad7 that facilitated CYLD deubiquitination of Smad7 at lysine 360 and 374 residues.

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Modified CYLD leads to the deubiquitination of RIPK1. 1 / 1

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As shown in XREF_FIG, CYLD overexpression caused RIP1 deubiquitination, which was exacerbated by selenite treatment.

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CYLD deubiquitinates E3_Ub_ligase. 1 / 1

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As it has previously been demonstrated that CYLD deubiquitinates TRAF6 these results suggests that CYLD deubiquitinates and suppresses the activity of both the E3 ligase and its kindred substrate [184[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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CYLD deubiquitinates NADP(+). 1 / 1

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CYLD Deubiquitinates Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Contributing to Adventitial Remodeling.

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CYLD deubiquitinates USP7. 1 / 1

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CYLD leads to the deubiquitination of FOS. 1 / 1

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CYLD suppresses AP1 function by regulating c-Jun and c-Fos ubiquitination.

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Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach

CYLD affects NFkappaB

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CYLD activates NFkappaB.

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CYLD activates NFkappaB. 10 / 10

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Although comparable CYLD mRNA levels were present in both tumor and normal tissue, direct binding of miR-182 to 3′UTR of CYLD activated NF-κB in tumor cells.

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However, subsequent studies have indicated that although CYLD targets NF-kappaB signaling factors, its function may depend on the cell type and stimulating receptor [XREF_BIBR].

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These miR then directly target the tumor suppressor genes, phosphatase and tensin homolog (PTEN) and cylindomatosis (CYLD), thereby promote NF-kappaB activity which is required to maintain the transformed state [XREF_BIBR].

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Across all solid tumor types, frequent inactivating TRAF3 and CYLD alterations that are predicted to constitutively activate NF-kappaB pathways, while inhibiting innate immunity, occur only in HPV+ HNSCC.

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The inhibition of NF-kappaB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TNFR associated factor 2 (TRAF2) and, to a lesser extent, TRAF6.

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miR-181b (activated by STAT3), has recently been identified as involved in a positive feedback loop by inhibiting CYLD (negative regulator of NF-kappaB), which in turn causes increased NF-kappaB, that completes the loop by leading to STAT3 activation.

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Further examination showed that phosphorylation of CYLD at S418 decreases its deubiquitinase activity and increases NF-kappaB activation.

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Deubiquitinases A20 and Cezanne, but not CYLD, are induced by NF-kappaB to negatively regulate TAK1 and NF-kappaB activity by removing K63 polyubiquitin chains [XREF_BIBR].

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In addition, NF-kappaB deubiquitinases CYLD and A20, which negatively regulate canonical NF-kappaB signaling, can induce NF-kappaB downstream of the BCR in miR-17 ~ 92 overexpressing B cells, and thus, have also been proposed as targets of oncomiR-1, [XREF_BIBR].

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The inhibition of NF-kB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TRAF2 and, to a lesser extent, TRAF6 [ xref ].

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Mutated CYLD activates NFkappaB. 3 / 3

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On the other hand, ectopic expression of CYLD mutants was found to elevate NF-kappaB activity in NPC cells, thus demonstrating a mutational drive for NF-kappaB signaling by CYLD aberrations in NPC.

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Our data also suggest that TRAF3 or CYLD mutations harbor episomal HPV and have activated NF-kappaB that may be required for episomal maintenance.

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Our data also suggest that TRAF3 or CYLD mutations harbor episomal HPV and have activated NF-kappaB, which may be required for episomal maintenance.

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CYLD-C601A activates NFkappaB. 1 / 1

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Also, activation of NF-kappaB by ectopic XIAP, an essential Ub ligase for NOD2 signaling, was blocked by overexpression of CYLD WT, but not CYLD C601A, which increased NF-kappaB activity (XREF_FIG D and XREF_SUPPLEMENTARY C).

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CYLD inhibits NFkappaB.

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CYLD inhibits NFkappaB. 10 / 10

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Our results show that reconsitituted expression of CYLD in miR-19a-replete cells only partially deactivates NF-kappaB, suggesting that CYLD might cooperate with other DUBs to switch off NF-kappaB signalling.

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CYLD has been shown to negatively regulate the activation of NF-kappaB XREF_BIBR.

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The results established that CYLD down-regulates NF-kappaB activation by TNF-alpha.

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For instance, CYLD negatively regulates NFkappaB activation and is involved in other immune response mechanisms.39 When TSGs such as CYLD are down-regulated, excessive inflammation occurs and tumorigenic factors can be promoted.40 Conversely, TSGs that were up-regulated were more likely to be involved in cell cycle regulation, apoptosis, and cell growth, possibly as a response to cell stress in early stages of tumorigenesis.

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Because CYLD inhibits NF-kappaB activation, it is probable that both PI3K-Akt and NF-kappaB signaling pathways are involved in CYLD regulated cell proliferation and survival.

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As both CYLD and OTULIN negatively regulate the NF-kappaB signalling cascade, the impact of these deubiquitinases in different LUBAC dependent signalling cascades may be context dependent.

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Interestingly, loss of CYLD causes constitutive NF-kappaB activation in developing NKT cells, which contributes to their defective IL-7 response and attenuated ICOS expression.

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When transfected in cell lines, CYLD inhibits the activation of NF-kappaB and mitogen activated protein kinases stimulated by innate immune receptors, such as the Toll like receptors and TNF receptors.

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CYLD inhibits activation of NF-kappaB by the TNFR family members CD40, XEDAR and EDAR in a manner that depends on the deubiquitinating activity of CYLD.

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NF-kappaB reporter assays in HeLa cells transiently transfected with pCruzCYLD1 or pHATRIP showed that CYLD inhibited in a dose dependent manner TNF-alpha-mediated activation of the NF-kappaB reporter gene similar to TRIP (XREF_FIG A).

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Mutated CYLD inhibits NFkappaB. 2 / 2

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Furthermore, nuclear translocation of Bcl-3, a component of reported NPC associated activated NF-kappaB signal p50/p50/Bcl -3, was inhibited upon CYLD WT expression, but not by CYLD mutants (XREF_SUPPLEMENTARY).

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Surprisingly, a non cleavable CYLD mutant does not impair TCR dependent canonical NF-kappaB activation, but does block activation of JNK, a critical step in TCR induced stimulation of multiple transcription factors and production of IL-2.

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CYLD-S418A inhibits NFkappaB. 1 / 1

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As observed in MCF-7 cells, however, CYLD S418A more strongly inhibited IKKepsilon induced NF-kappaB activation.

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CYLD bound to Tax inhibits NFkappaB. 1 / 1

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We found that Tax interacts with CYLD, a deubiquitinase that negatively regulates NF-kappaB activity, by inactivating it.

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CYLD affects MAP3K7

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CYLD inhibits MAP3K7.

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CYLD inhibits MAP3K7. 10 / 10

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This is explained by loss of CYLD mediated TAK1 K63 deubiquitination [XREF_BIBR], which suppresses TAK1 activation in wild-type lymphocytes (XREF_FIG).

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Conversely, loss of the K63 specific deubiquitinase CYLD causes spontaneous activation of IKK and JNK as well as their upstream kinase Tak1.

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Genetic deletion of CYLD or ITCH, essential ubiquitin regulators for TAK1 deactivation, causes strong and sustained TAK1 activation with enhanced production of tumor promoting proinflammatory cytokines that mediate liver fibrosis, tumor development, and metastasis [XREF_BIBR, XREF_BIBR].

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161 Cylindromatosis (CYLD) has been shown to inhibit NFkappaB activation 160 and more recent results indicate that this inhibition might be mediated via the ability of CYLD to hydrolyze unanchored polyubiquitin chains and thus inhibit TAK1 and IKK activation.

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The loss of CYLD in T cells causes constitutive activation of TAK1 and its downstream signalling molecules, IKK and JNK (JUN N-terminal kinase).

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In keeping with a previous finding that Tak1 ubiquitination mediates its autoactivation, we have shown that CYLD potently inhibits the catalytic activity of Tak1 in transfected cells.

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Thus, CYLD prevents excessive activation of TAK1 and p38, which results in reduced FOXP3 expression and Treg generation.

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Additionally, in both macrophages and T cells, CYLD inhibits the ubiquitylation and subsequent activation of Tak1, a kinase that activates both IKK and JNK.

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The fact that loss of CYLD causes spontaneous activation of TAK1 implies that TAK1 ubiquitylation is a dynamic event that occurs even in resting T cells.

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Deubiquitinases A20 and Cezanne, but not CYLD, are induced by NF-kappaB to negatively regulate TAK1 and NF-kappaB activity by removing K63 polyubiquitin chains [XREF_BIBR].

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CYLD-Y485A bound to ITCH inhibits MAP3K7. 2 / 2

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Reconstitution of wild-type Cyld but not the mutant Cyld (Y485A), which can not associate with Itch, blocked sustained Tak1 activation and proinflammatory cytokine production by Cyld (-/-) bone marrow derived macrophages.

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Reconstitution of wild-type Cyld but not mutant Cyld (Y485A), which can not associate with Itch, blocked the sustained Tak1 activation and proinflammatory cytokine production by Cyld -/- bone marrow derived macrophages.

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CYLD inhibits ubiquitinated MAP3K7. 1 / 1

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Loss of CYLD causes accumulation of ubiquitinated TAK1 and aberrant TAK1 activation.

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CYLD bound to ITCH inhibits MAP3K7. 1 / 1

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This finding suggests that Itch and Cyld complex degrades the Tak1 that is associated with TRAF complex but not the entire pool of Tak1 within the cell during an inflammatory response.

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CYLD activates MAP3K7.

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CYLD activates MAP3K7. 10 / 10

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In an analysis of the mechanism of this finding, we noted first that TGF-beta-stimulated T cells lacking CYLD exhibit increased TAK1 and p38 mitogen activated protein kinase (MAP kinase) activity.

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Reconstitution of Cyld -/- MEFs with Cyld (WT) restored transient Tak1 activation (XREF_FIG) and normalized IL-6 production.

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Thus, it was logical to examine whether CYLD targets Tak1 and regulates its ubiquitination.

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CYLD targets and inhibits the ubiquitin dependent IKKbeta kinase TAK1 and therefore prevents aberrant lymphocyte activation [XREF_BIBR, XREF_BIBR], while A20 dampens NF-kappaB activity by trimming K63-ubiquitin chains attached to MALT1 [XREF_BIBR, XREF_BIBR].

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In mature T cells, CYLD targets TAK1 for inactivation to downregulate IKK and NF-kappaB activation [XREF_BIBR].

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Deubiquitinases A20 and Cezanne, but not CYLD, are induced by NF-kappaB to negatively regulate TAK1 and NF-kappaB activity by removing K63 polyubiquitin chains [XREF_BIBR].

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XREF_BIBR, XREF_BIBR Similarly, in a hepatocytespecific cylindromatosis deficient (CYLD Deltahep) mouse model, which typically has increased hepatocyte TAK1 and NF-kappaB activation, TAK1 deletion decreased HCC development.

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It has been reported that an adequate amount of CYLD impairs the progression of NASH by inhibiting TAK1 signaling, and the E3 ligase TRIM47 has been revealed to be a key regulator of CYLD degradation, revealing that both of the above targets could be significant for the treatment of NAFLD.92 Caspase Inhibitor : Emricasan is a caspase inhibitor which can reduce the portal hypertension via blocking the activation of inflammatory caspase and inhibiting hepatocyte cell death.

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By using CYLD knock-out mice, a recent study shows that in TGF-beta-treated T cells, CYLD deficiency causes enhanced TAK1 and p38 mitogen activated protein kinase activities.

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Deficiency in ITCH or CYLD causes sustained activation of TAK1 and increased cytokine production in bone marrow derived macrophages, and tumorigenesis and metastasis of transplanted Lewis lung carcinoma, suggesting that sustained activation of TAK1 leads to the progression of non-small-cell lung cancer (NSCLC) [XREF_BIBR].

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CYLD decreases the amount of MAP3K7.

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Modified CYLD decreases the amount of MAP3K7. 1 / 1

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Surprisingly, we found that overexpression of FLAG-CYLD failed to inhibit TAK1 and TAB1 overexpression induced TAK1 polyubiquitination (XREF_FIG).

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CYLD affects CXCL8

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CYLD decreases the amount of CXCL8.

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CYLD decreases the amount of CXCL8. 10 / 10

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Addition of CYLD siRNA to A20 siRNA further increased the IL-8 mRNA expression suggesting additive effects of CYLD and A20.

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Addition of CYLD siRNA to A20 siRNA further increased the IL-8 mRNA expression in tolerant cells suggesting additive effects of CYLD and A20.

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Together, these data suggest that CYLD negatively regulates IL-8 expression by specifically targeting the ERK signaling pathway.

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CYLD negatively regulates nontypeable Haemophilus influenzae induced IL-8 expression via phosphatase MKP-1-dependent inhibition of ERK.

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Having demonstrated that CYLD suppresses NTHi induced IL-8 expression, we next aimed to investigate the mechanism through which this regulation occurs.

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We next sought to determine whether CYLD inhibits upregulation of IL-8 expression induced by direct activation of ERK using a constitutively active form of MEK (MEK-CA).

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In this study, we demonstrated that CYLD strongly suppressed NTHi induced IL-8 expression in human lung epithelial cells.

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Importantly, we determined that CYLD negatively regulates ERK dependent IL-8 expression specifically by inducing MKP-1 expression.

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Here, we show that CYLD suppresses NTHi induced IL-8 expression by specifically targeting the activation of ERK.

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We further demonstrated that CYLD decreased IL-8 levels via inactivation of the ERK signaling pathway.

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Modified CYLD decreases the amount of CXCL8. 2 / 2

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As shown in XREF_FIG, DUB activity deficient CYLD mutant (CYLD H/N) had no effect on NTHi induced MKP-1 and IL-8 expression, whereas overexpression of CYLD WT enhanced MKP-1 induction and suppressed IL-8 expression.

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Moreover, overexpression of CYLD WT suppressed, whereas CYLD knockdown by siCYLD enhanced, MEK-CA-induced IL-8 expression (XREF_FIG and XREF_SUPPLEMENTARY).

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Additionally, similar result was also observed in human cervical epithelial HeLa cells (XREF_SUPPLEMENTARY), which further suggests the generalizability of inhibition of IL-8 by CYLD.

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As shown in XREF_FIG, IL-8 induction is markedly inhibited by CYLD WT.

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Additionally, similar result was also observed in human cervical epithelial HeLa cells ( xref ), which further suggests the generalizability of inhibition of IL-8 by CYLD.

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MKP-1 and CYLD can synergistically inhibit production of neutrophil chemoattractant IL-8 from airway epithelial cells.

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To further elucidate the role of CYLD in IL-8 levels, we used the specific MEK inhibitor, PD98059, to examine the involvement of the ERK pathway in CYLD mediated suppression of IL-8.

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Furthermore, the CYLD overexpressed H460 cells were treated with 100ng/mL of TNF-alpha in combination with different concentrations of Nec-1 for 24 hours, including 0muM, 0.1 muM, 1.0 muM, and 10muM, respectively (XREF_FIG).

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Immunoprecipitation of FADD from CYLD expressing and control Cyld -/- MEFs treated with TNF in the presence of zVAD-fmk revealed that recruitment of RIPK1 to the FADD necrosome is strictly dependent on CYLD (XREF_FIG).

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CYLD mRNA is upregulated by TNF alpha and bacterium nontypeable Haemophilus influenza, providing evidence for an inducible autoregulatory feedback loop controlling CYLD expression (Jono et al., 2004).

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In addition, TRAF2 and TRAF6 appear to be differentially involved in NF-kappaB-dependent induction of CYLD by TNF-alpha and NTHi.

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However, although A20 and CYLD are induced by TNFalpha for the establishment of a negative feedback loop, neither OTULIN (XREF_FIG F) nor LUBAC are induced by TNFalpha, again suggesting that they function as a differentially regulated signaling module.

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The stable cell line of CYLD overexpressing A549 cells was treated with 10ng/mL of TNF-alpha alone, or 20ng/mL of TNF-alpha combinated with 10muM of a pancaspase inhibitor, z-VAD-fmk, for 12 hours, and the cell apoptosis rate and necrosis rate were determined by Annexin v-FITC/PI dual staining analysis following the kit protocols (Santa Cruz, USA).

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On the other hand, CYLD also acts as a mediator of immune activation and inflammation.38, 39 We found that both SPATA2 and CYLD are induced by TNF-alpha and IL-1beta in vitro, indicating a similar regulation in OC.

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After 48 h of infection, cells were transfected with CYLD expression plasmid or left untransfected and treated with TNFalpha for 10 min after 30 h of transfection.

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Furthermore, NF-kappaB-dependent induction of CYLD by TNF-alpha triggers an autoregulatory feedback mechanism through deubiquitylation of TRAF2 and TRAF6 [37].

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Knockdown of CYLD had no effect on cell death of NEMO deficient cells treated with TNF in the absence of zVAD, i.e. CYLD is not required when the cell death is apoptotic (XREF_FIG).

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Indeed, both TNF-alpha and non typeable Haemophilus influenzae (NTHi), a common Gram negative bacterial pathogen that causes respiratory infections, can upregulate CYLD expression, suggesting that CYL[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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At this time, the underlying mechanism by which TNFalpha up-regulates the expression of CYLD is not clear.

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Such a function of CYLD was suggested by the finding that the expression of CYLD is induced by proinflammatory cytokines, TNF-alpha and IL-1beta, and the Gram negative bacterium Haemophilus influenzae.

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32 In mouse bone marrow derived macrophages, CYLD expression is strongly induced by RANKL, but not by TNF-alpha or LPS.

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In cultured human tubular epithelial HK-2 cells, tumor necrosis factor-alpha (TNFalpha) up-regulated CYLD expression.

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The expression of CYLD can be induced by TNF treatment or viral infection (Friedman et al., 2008) .

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The expression of CYLD and NF-kappaB mRNAs in HSG cells was increased by TNF-alpha.

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For example, although TNF-alpha stimulates CYLD expression in HeLa cells, human bronchial epithelial cells, and human aortic endothelial cells, XREF_BIBR - XREF_BIBR it fails to induce CYLD expression in 293 cells.

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One possibility is that Cyld expression is upregulated by TNF and IL-1beta, via IKK-NF-kappaB pathway XREF_BIBR, XREF_BIBR, XREF_BIBR triggers its association with Itch.

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Another protein, CYLD which deubiqitinates TRAF6, and is negatively regulated by specific TNF receptors, might play a role of a silencer of EDAR signaling, since mutations in CYLD predispose not only to skin tumors (cylidromatosis), but also to the development of tumors of eccrine sweat glands and hair follicles.

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This model is consistent with the recent discovery that caspase 8 mediated cleavage of CYLD limits TNF induced programmed necrosis [XREF_BIBR], since caspase 8 is present in the necrosome, but not the TNFR-1 complex.

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Inhibiting CASPASE-8 leads to CYLD dependent necroptosis caused by the TNF produced in response to TLR4 ligation.

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CASP8 affects CYLD

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CASP8 inhibits CYLD.

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We identified cFLIP upregulation that may promote caspase 8 mediated degradation of CYLD, and other necrosome components, as a possible mechanism abrogating Mtb 's capacity to coopt necroptotic signaling.

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Co-transfection of HEK 293 cells revealed that over-expression of wild-type CASPASE 8, but not the catalytically inactive mutant CASPASE 8-C360S, causes degradation of CYLD protein (XREF_FIG).

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Neither RIPK1 nor RIPK3 was required for the processing of CYLD to CYLDp25 in MEFs (XREF_SUPPLEMENTARY), indicating that CASPASE 8 inactivation of CYLD occurs upstream of these necrosome components.

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Neither RIPK1 nor RIPK3 were required for CYLD cleavage, and CYLD inactivation by casp8 is proposed to occur upstream of RIPK activity.

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Neither RIPK1 nor RIPK3 were required for CYLD cleavage, and CYLD inactivation by casp8 is proposed to occur upstream of RIPK activity.

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Active caspase-8 has been reported to inhibit necroptosis by cleaving RIPK1, RIPK3, and CYLD XREF_BIBR - XREF_BIBR.

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In contrast, loss of CASPASE 8 prevented CYLD degradation resulting in necrotic death.

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Neither RIPK1 nor RIPK3 was required for the processing of CYLD to CYLDp25 in MEFs ( xref ), indicating that CASPASE 8 inactivation of CYLD occurs upstream of these necrosome components.

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Caspase 8 then cleaves and inactivates RIPK1, RIPK3 and CYLD and stimulates apoptosis.

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Since caspase 8 is not recruited to the membrane-anchored TNFR-1 complex where CYLD is supposed to exert its effect [ xref , xref ], caspase 8 should not be able to cleave and inhibit CYLD at this complex.

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Therefore, removal of CYLD-WT by CASPASE 8 prolongs the ubiquitination state of RIPK1 and maintains RIPK1 in a pro-survival complex with NEMO. In contrast, the resistance of CYLD-D215A to proteolytic cleavage by CASPASE 8 resulted in less ubiquitination of RIPK1 (Figure 5), which enhanced RIPK1 interaction with the necrosome to initiate death (Figure 4). These observations demonstrate that CASPASE 8 cleavage of CYLD functions as a pro-survival event by preventing CYLD from deubiquitinating RIPK1

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CASP8 activates CYLD.

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Following TNF stimulation, aberrant CYLD necroptotic activity is held in check by caspase-8 mediated CYLD processing and inactivation 74.

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An alternative explanation for the embellished necroptotic sensitivity observed in casp8 deficient cells has been raised by Ting and colleagues, observing that casp8 mediated cleavage of the E3 ubiquitin ligase CYLD enhances RIP1 and RIP3 dependent necroptosis [XREF_BIBR].

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Necroptotic signaling is also suppressed by caspase 8 mediated cleavage of RIPK1 and/or CYLD.

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XREF_BIBR, XREF_BIBR Second, caspase 8 mediated cleavage of CYLD generates a survival signal, whereas the mutation of caspase 8 mediated cleavage site on CYLD switches cell survival to necrotic cell death in response to TNFalpha.

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In normal circumstances, caspase-8 molecule activates apoptosis by blocking the necroptosis and by cleaving RIPK1 and CYLD [XREF_BIBR - XREF_BIBR].

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Caspase-8 and FADD in tandem inhibit necroptosis by inhibiting the activity of RIPK1 and RIPK3 and CYLD and promote the advent of apoptosis via the cleavage of PARP-1 [XREF_BIBR, XREF_BIBR].

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Caspase-8 also targets the deubquitinase CYLD preventing RIPK1 initiation of necroptosis [XREF_BIBR, XREF_BIBR].

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Levels of CYLD may be indirectly increased by allosteric inhibition of caspase 8 (which cleaves CYLD) by zVAD-FMK [XREF_BIBR].

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Blockade of Caspase 8 activity with the pharmacological inhibitor IETD prevents the loss of full-length CYLD and this correlates with the entry of the NEMO deficient cells into cell death by programmed necrosis.

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CYLD affects inflammatory response

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CYLD inhibits inflammatory response.

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In a similar study, CYLD was shown to negatively regulate NF-kappaB activation and lung inflammation in mice infected with non typeable Haemophilus influenzae 22.

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Recent insights into the normal functions and signaling interactions of the CYLD gene product indicate that CYLD interferes with NF-kappaB, JNK, and p38MAPK signaling to limit inflammation and cancer,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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For example, CYLD has been shown to downregulate the inflammatory response following bacterial infection with Escherichia coli by negatively regulating the innate immune response via inhibition of NF-kappaB signalling.

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Reduced expression of CYLD promotes cell survival and inflammation in gefitinib treated NSCLC PC-9 cells : targeting CYLD may be beneficial for acquired resistance to gefitinib therapy.

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CYLD also inhibited inflammation and proliferation in vascular cells and represented a novel target for the treatment or prevention of atherosclerosis [XREF_BIBR].

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NTHi induced CYLD, in turn, negatively regulates NTHi induced NF-kappaB activation through deubiquitinating TRAF6 and 7 and down-regulates inflammation.

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Focusing on recent data concerning the normal functions and signaling interactions of the CYLD gene product, we explain how CYLD interferes with TNF-alpha or TLR mediated signaling as well as with JNK or NF-kappaB-dependent p65/50 signaling to limit inflammation.

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Previous studies indicate that CYLD overexpression reduced inflammation during acute or chronic liver injury.

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CYLD suppresses NF-kappaB-dependent inflammation by removing K63 linked polyubiquitin chains from TRAF2, TRAF6, NEMO, TAK1, Bcl3 and RIP1.

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Although additional studies are needed to clarify the molecular mechanisms, our in vitro data suggested that hypoxia induced CYLD reduction may promote inflammation in an autocrine and paracrine fashion in GBM tissues.

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CYLD activates inflammatory response.

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Indeed, it was found that deletion of CYLD -- which is required for RIPK activation downstream of TNF -- prevented inflammation caused by intestinal deletion of FADD, but not of NF-kB signaling 75.

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These results suggest that PDE4B negatively regulates CYLD expression and mediates inflammation via the JNK pathway.

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Adoptive transfer of CYLD KO T cells into RAG KO mice that lack endogenous lymphocytes induced autoimmune symptoms and intestinal inflammation.

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Hypoxia suppresses cylindromatosis (CYLD) expression to promote inflammation in glioblastoma : possible link to acquired resistance to anti-VEGF therapy.

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Taken together, it is evident that PDE4B negatively regulates CYLD expression and mediates NTHi induced inflammation via specific activation of JNK2 but not JNK1 pathway.

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Thus, we sought to determine whether increased cAMP does have an important role in inhibiting JNK2 activation, which in turn enhances CYLD expression and suppresses inflammation.

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Inactivation of the deubiquitinase CYLD in hepatocytes causes apoptosis, inflammation, fibrosis, and cancer.

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NTHi induced CYLD expression, which in turn leads to negative regulation of NTHi induced NF-kappaB-dependent inflammation [XREF_BIBR].

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Adoptive transfer of Cyld -/- T cells induces autoimmune symptoms and colonic inflammation in recipient mice.

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Knockdown of CYLD rescued compromised inflammatory response of macrophages induced by Notch blockade in I/R injury in vitro.

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CYLD affects cell population proliferation

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CYLD inhibits cell population proliferation.

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As we expected, the MTT assay results showed that overexpression of CYLD obviously decreased the proliferation of A549 cells or H460 cells compared with that of untreated cells (* p < 0.05, ** p < 0.01).

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71 The gene CYLD is mutated in familial cylindromatosis, an autosomal dominant disease characterized by benign tumors derived from cells of skin appendages 72 and thus it can be considered as a TS, CYLD inhibits tumor cell proliferation by blocking BCL-3-dependent NF-kappaB signaling.

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Ectopic expression of CYLD wild-type gene suppressed C666-1 cell proliferation (XREF_FIG) and anchorage independent growth on soft agar (XREF_FIG), while expression of patient derived CYLD point and truncating mutations resulted in the loss of these tumour-suppressive activities (XREF_FIG).

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MiR-501-5p upregulation corresponded with a downregulation of CYLD in the same tissues and cell lines, and overexpression of MiR-501-5p decreased CYLD expression, increased expression of cyclin D1 and c-myc and promoted the proliferation of hepatocellular carcinoma cells in vitro.

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Full length CYLD but not CYLD C/S could significantly reduce proliferation rate of CYLD-/- MEFs after 72 hours (XREF_FIG) indicating that the deubiquitinating activity of CYLD is required for the observed phenotype.

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CYLD inhibits proliferation and metastasis of melanoma cells in vivo.

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CYLD also inhibited inflammation and proliferation in vascular cells and represented a novel target for the treatment or prevention of atherosclerosis [XREF_BIBR].

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For instance, deubiquitinating enzyme, CYLD (Cylindromatosis tumor suppressor gene) is believed to suppress cell proliferation and tumorigenesis by removing K63 linked ubiquitin chains from TRAF2 and IKKgamma thereby inhibiting NF-kappaB activation XREF_BIBR.

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As a result, loss of CYLD enhances basal ubiquitination, membrane recruitment and activation of Akt, thereby promoting cell proliferation, cell survival and glucose uptake, which are all important pro tumorigenic events.

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Cyld inhibits tumor cell proliferation by blocking Bcl3-dependent NFkB signaling.

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Silencing of CYLD expression reversed the cell proliferation promotion by miR-1288-in in GBM.

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Catalytic domain mutation in CYLD inactivates its enzyme function by structural perturbation and induces cell migration and proliferation.

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The present study investigated whether abnormal ectopic CYLD expression is sufficient to promote the proliferation of HCC827 and Calu-3 cells.

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CYLD downregulation reversed the inhibitory effects of the proliferation of melanoma cells A375 and WM35 after transfection with miR-767-in.

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Interestingly, in melanoma cells, SNAIL has been shown to inhibit expression of CYLD, which in turn leads to increased melanoma proliferation and invasion [XREF_BIBR].

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In this study we demonstrate that lack of CYLD expression in CYLD-/- MEFs increases proliferation rate of these cells compared to CYLD +/+ in a serum concentration dependent manner without affecting cell survival.

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Knockdown of CYLD promoted cell proliferation of lung cancer cells.

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Elimination of SRF by siRNA or inhibition of p38 MAPK reduced the expression level of CYLD and increased cell proliferation.

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To conclude, we found that downregulation of CYLD induces tumor cell proliferation, consequently contributing to the aggressive growth of HCC.

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CYLD deficiency also promoted cancer cell proliferation, survival, glucose uptake, and, when injected into mice, growth of prostate tumors.

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CYLD affects apoptotic process

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CYLD inhibits apoptotic process.

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CYLD inhibits apoptotic process. 10 / 10

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Reversely, overexpression of CYLD could promote cell apoptosis, whereas inhibiting cell proliferation and antibody production.

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Here we show that genetic deficiency of Cyld, a recently identified deubiquitinating enzyme, attenuates the early wave of germ cell apoptosis and causes impaired spermatogenesis in mice.

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To our surprise, amputation induced apoptosis was increased by RNAi of tak1 or p38-1, and decreased by RNAi of cyld-1 (XREF_FIG).

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CYLD (C/S) tumors are also characterized by their elevated proliferation rate and decreased apoptosis.

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Liver specific deletion of CYLD exon9 (CYLD lox and lox / ALFP-Cre) induces spontaneous apoptosis of periportal hepatocyte, and subsequent HSC and Kupffer cell activation, thereby triggering fibrosis, inflammation, and TNFalpha production [XREF_BIBR, XREF_BIBR].

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LEF1 mediated inhibition of CYLD expression is abolished upon selenite treatment to trigger apoptosis.

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Furthermore, we uncovered a dual function of CYLD in the pathogenesis of ECM : (i) CYLD impaired activation of PKC-theta and NF-kappaB in CD8 + T cells and (ii) CYLD promoted apoptosis of endothelial cells, thereby augmenting brain pathology and preventing survival during ECM.

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Flow cytometry further revealed that CYLD siRNAs inhibited both early and late apoptosis induced by noscapine in CCRF-CEM cells.

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CYLD and cellular inhibitors of apoptosis (cIAPs) are involved in CD40 mediated cell death.

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As shown in XREF_FIG, upon selenite treatment, cIAPs were degraded, and CYLD transcription was upregulated, causing degradation of RIP1 K63 ubiquitin chains and subsequent DISC formation, caspase-8 activation and apoptosis.

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CYLD activates apoptotic process.

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Loss of CYLD inhibits cellular apoptosis by activating NF-kappaB pathway [XREF_BIBR].

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Increased expression of CYLD in BT549 cells induced apoptosis, while its suppression by small interfering RNA inhibited cell death in BAF57 expressing BT549 cells.

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In addition, CYLD overexpression markedly increased apoptosis of HCC827 and Calu-3 cells (XREF_FIG).

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Taken together, our data show that the presence of CYLD promotes brain pathology with increased neuroinflammation and hemorrhage as well as endothelial cell activation and apoptosis.

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Increasing CYLD promotes apoptosis and increasing PNUTL enhances cell death via TGF.

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Firstly, we asked whether overexpression of CYLD-flag could induce cell apoptosis, which probably contributed to CYLD induced cell death.

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Consistently, CYLD expressing tumors had features of reduced cell proliferation and enhanced cell apoptosis as indicated by the decreased number of Ki-67-positive cells and the increased number of caspase-3-positive cells, respectively (XREF_FIG, XREF_SUPPLEMENTARY).

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This results in inhibition of NF-kappaB activation and loss of CYLD is shown to inhibit apoptosis.

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Our findings underscore a putative mechanism whereby CYLD repression mediated and NF-kappaB transactivation dependent miR-19a regulatory feedback loop prevents cell apoptosis in response to OS microenvironment.

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The results demonstrated that miR-454 downregulated CYLD mRNA and protein expression which increased the apoptosis rate of cancer cells.

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NFkappaB affects CYLD

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NFkappaB activates CYLD.

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The NF-kappaB activation in CYLD deficient thymocytes is independent of CARMA1, because the NF-kappaB activation was also detected in CYLD and CARMA1 double knock-out thymocytes.

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9 These data suggest that CYLD controls inflammation through TRAF signaling and NF-kappaB p65 and p50 activation or cellular proliferation through Bcl-3 activation and NF-kappaB p50 and p52 binding.Re[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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On the other hand, activated NF-kappaB stimulates transcriptional upregulation of CYLD to antagonize TRAF6 by promoting its K63 linked deubiquitination, presenting a negative feedback loop of NF-kappaB activation [XREF_BIBR].

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Of the 128 screened siRNA pools, 15 matched these criteria including those targeting the known negative regulators of NF-kappaB signalling CYLD and A20.

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As such, RIPK1 deubiquitination is mediated by a range of multiple deubiquitinating enzymes (DUBs) such as A20 and cylindromatosis (CYLD), which are upregulated by NF-kappaB at excessive intracellular concentrations of TNF-alpha [XREF_BIBR, XREF_BIBR].

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On the other hand, mice that express overactive NF-kappaB or lack the negative regulator of NF-kappaB signaling CYLD, develop NKT cells but fail to mature and populate the lymphoid organs and peripheral tissues.

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Supporting evidence for NF-kappaB- dependent upregulation of CYLD was provided by genomic sequence analysis that revealed NF-kappaB binding sites within the CYLD promoter region [37].

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NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB : evidence for a novel inducible autoregulatory feedback pathway.

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This results in inhibition of NF-κB activation and loss of CYLD is shown to inhibit apoptosis (Trompouki et al., xref ; Figure xref ).

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These data suggest that activation of Notch signaling in myeloid cells aggravates I/R injury, by enhancing the inflammation response by NF-kappaB through down regulation of CYLD.

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This is also illustrated by the more than 100-fold increase of CFU in both NF-kappaB inhibited WT and Cyld -/- BMDM as compared to a < 10-fold increase in macrophages with ERK1/2 inhibition.

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These findings suggested that, by upregulating the expression of miR-130b and consequently inhibiting CYLD, NF-κB sustained its persistent activation and stimulated the progression of bladder cancer.

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If NFkappaB upregulates miR-19, relative to CYLD, this pathway ultimately allows for the sustained activation of NFkappaB in T-ALL through the miR-19 mediated inhibition of CYLD [XREF_BIBR].

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Similar to A20, the UCH-type deubiquitylating enzyme CYLD limits NF-kappaB activation by deubiquitylation.

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Whether CYLD expression can be induced by NF-kappaB specifically following DNA damage as a means of feedback inhibition remains to be determined.

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To determine the role of CYLD in NF-kappaB signaling of cholesteatoma, CYLD and NF-kappaB expression levels in middle ear cholesteatoma epithelium were examined by immunohistochemical analysis to determine protein level and localization and compared to those of normal retroauricular (RA) skin.

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For instance, the transcription of CYLD is induced by activation of the NF-kappaB and MKK3/6-p 38 pathways Post-translational covalent modifications.

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NFkappaB decreases the amount of CYLD.

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However, a recent report showed that the loss of CYLD in keratinocytes of mice did not affect transcription induced by the classical p65-p50 NF-kappaB dimers but had clear effects on Bcl-3-linked p50- or p52 dependent gene regulation [XREF_BIBR].

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Thus, the present study revealed that, in bladder cancer, NF-kappaB can maintain its activity by establishing a feedback loop, in which NF-kappaB induced the expression of miR-130b, which consequently inhibited the expression of CYLD, which in turn was an endogenous inhibitor of NF-kappaB activation.

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Interestingly, the reduced NF-kappaB activation in CYLD expressing macrophages limited the protective effect of IFN-gamma by reducing NF-kappaB-dependent signal transducers and activators of transcription-1 (STAT1) activation.

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CYLD affects CYLD

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CYLD inhibits CYLD.

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Additionally, phosphorylation of CYLD was found to downregulate CYLD activity : transient phosphorylation by IKK in a serine cluster just upstream of the TRAF2 binding site, attenuates DUB function XREF_BIBR.

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These results demonstrate that phosphorylation of CYLD at Ser418 suppresses CYLD activity, resulting in increased NF-kappaB transcriptional activation.

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The CYLD staining and protein expression were lower in the OX-LDL+ Sal A group than OX-LDL group after culturing for 48 hours (P < 0.01, Figures XREF_FIG - XREF_FIG and XREF_FIG), revealing that OX-LDL increases CYLD level and Sal A antagonizes OX-LDL by downregulating CYLD.

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Together, these observations demonstrate that IKKepsilon mediated phosphorylation of CYLD at Ser418 inhibits CYLD deubiquitinase activity.

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As IKK mediated phosphorylation of CYLD has been reported to negatively regulate CYLD enzymatic activity [XREF_BIBR], we further explored whether IKK is also involved in regulating the degradation of CYLD by SCF beta-TRCP.

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Phosphorylation of CYLD at Ser418 decreases CYLD activity.

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However, constitutive phosphorylation of CYLD by IKK inactivates CYLD in HTLV-1-induced leukemia to promote heightened NF-kappaB activation.

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CYLD bound to CEP350 inhibits CYLD. 1 / 1

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In transgenic mice engineered to mimic the smallest truncation found in cylindromatosis patients, CYLD interaction with CAP350 is lost disrupting CYLD centrosome localization, which results in cilia formation defects due to impairment of basal body migration and docking.

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Adenoviral over-expression of CYLD shRNA (20 MOI) completely inhibited CYLD protein expression.

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Western blotting and a dual-luciferase reporter assay were used to verify that miR-1288 targets CYLD by interacting with the 3 ' UTR of CYLD to reduce CYLD expression.

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To further confirm CYLD as a target for human melanoma, specific si-RNAs of CYLD were used to inhibit CYLD expression in both melanoma cells A375 and WM35, respectively.

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Adenoviral over-expression of CYLD shRNA dose-dependently inhibited CYLD mRNA expression with an efficacy of> 90% knockdown of endogenous CYLD at dose of 10 multiplicity of infection (MOI) in HK-2 cel[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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CYLD bound to LEF1 decreases the amount of CYLD. 1 / 1

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Our study showed that LEF1 binds the CYLD promoter and suppresses endogenous CYLD levels, whereas selenite caused LEF1 to dissociate from the CYLD promoter.

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CYLD increases the amount of CYLD.

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CYLD increases the amount of CYLD. 4 / 4

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The relative expression levels of CYLD following CYLD overexpression in A549 cells and H460 cells were significantly higher (3.37 +/- 0.16 and 2.67 +/- 0.17 times), compared with that in pcDNA3.1 plasmid transfected A549 and H460 cells.

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The p38 and CYLD pathway is involved in neuronal necroptosis induced by OGD injury and the p38 and CYLD pathway can be activated to increase CYLD protein expression.

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BCL3 was identified as a CYLD specific substrate in BCC and treatment of BCC cell lines with cyclopamine rescued the expression of CYLD.

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That is, inhibition of endogenous CYLD expression by CYLD siRNA in C33A cells (XREF_FIG) abrogated the hypoxia induced NF-kappaB activation associated with ectopic E6 expression (XREF_FIG).

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CYLD activates CYLD.

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CYLD activates CYLD. 2 / 2

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IKKɛ also phosphorylates and inactivates the tumor suppressor CYLD, preventing CYLD from deubiquitinating specific substrates in the NF-κB signaling pathway.

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IKKe also phosphorylates and inactivates the tumor suppressor CYLD, preventing CYLD from deubiquitinating specific substrates in the NF-kB signaling pathway.

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CYLD affects BCL3

1 | 1 16

CYLD inhibits BCL3.

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CYLD inhibits BCL3. 10 / 10

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Interestingly, the ubiquitin ligase CYLD, which negatively regulates bcl3 nuclear localization, was increased 2.7-fold in the RNA-Seq analysis (XREF_SUPPLEMENTARY).

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CYLD prevents nuclear accumulation of BCL-3 and hence reduces Cyclin D1 expression and proliferation of keratinocytes.

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CYLD inhibits Bcl3 by antagonizing the K63-linked polyubiquitination of Bcl3 thus preventing its nuclear translocation.

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CYLD, but not C/S-CYLD, abrogated BCL-3 binding of IL-10 promoter, confirming the important role of CYLD in the regulation of BCL-3.

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Furthermore, siRNA against Snail1, which up-regulated CYLD expression (XREF_FIG), reduced nuclear BCL-3 levels, confirming that reexpression of CYLD blocks nuclear translocation of BCL-3 in melanoma (XREF_FIG).

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Here, decreasing CYLD levels activated BCL3 accumulation followed by its import into the nucleus, probably mediated by an interaction between the polyubiquitin chains of BCL-3 and importins.

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It was observed in malignant melanoma that loss of CYLD also induces nuclear accumulation of BCL-3 and NF-kappaB activation, with the consequence of induced N-cadherin (migration) and cyclin D1 (proliferation) activity.

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CYLD negatively regulates BCL3, preventing nuclear entry where it forms a dimer with p50 and p52, resulting in transcription of genes involved in proliferation including cyclin D1.

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CYLD inhibits Bcl3 by antagonizing the K63 linked polyubiquitination of Bcl3 thus preventing its nuclear translocation.

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CYLD inhibits ubiquitinated BCL3. 1 / 1

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1 | 1 2 6

CYLD inhibits TRAF6. 10 / 10

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As shown in XREF_SUPPLEMENTARY, CYLD knockdown, using siCYLD, still enhanced TGF-beta-induced fibrotic response in TRAF6 depleted cells, thereby suggesting that CYLD inhibits Akt mediated fibrotic response at least in part by directly interacting with and deubiquitinating Akt.

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The ubiquitin-editing enzyme CYLD inhibits TRAF6 and -7 and TLR2 [ xref ].

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As we described here for YOD1, CYLD is acting on TRAF6 and p62 complexes, but - in contrast to YOD1 - CYLD is not preventing the formation of TRAF6 and p62 aggregates, but is recruited to TRAF6 by p62.

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TRAF6 are inhibited by A20, CYLD and OTUB2 that specially remove TRAF6 K63‐linked ubiquitination.

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TRAF6 are inhibited by A20 , CYLD and OTUB2 that specially remove TRAF6 K63-linked ubiquitination .

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Similarly, de-ubiquitinating enzyme cylindromatosis (CYLD) inhibits NF-kappaB signaling via de-ubiquitination and inactivation of TNFR associated factor 2 (TRAF2) and TRAF6 [XREF_BIBR, XREF_BIBR]; de-ubiquitinating protease A20 inhibits NF-kappaB activation induced by Toll like receptor 4 (TLR4) via removing K63 linked polyubiquitin chains of TRAF6 [XREF_BIBR].

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The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6.

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Thus, it is possible that CYLD functions in diverse pathways and loss of CYLD activity contributes to tumorigenesis via multiple mechanisms.Lys63-linked ubiquitin chains, synthesized in response to cy[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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TRAF6 are inhibited by A20, CYLD and OTUB2 that specially remove TRAF6 K63‐linked ubiquitination.

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Further, the de-ubiquitinase CYLD has been shown to inactivate TRAF6 downstream of RANK in osteoclasts, as evidenced by removal of polyubiquitin chains, and the physiologic relevance of this mechanism is supported by the phenotype of CYLD deficient osteoclasts, which exhibit hyper-responsiveness to RANK.

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CYLD activates TRAF6.

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CYLD activates TRAF6. 7 / 7

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CYLD has been shown to target TRAF6, TRAF2, and NEMO for deubiquitination, thus presumably reduced their activities in NF-kappaB activation.

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40 RANKL stimulated osteoclastogenesis potently induces the expression of CYLD, and the accumulated CYLD targets TRAF6 by interacting with the adaptor protein, p62.

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More importantly, we showed that TRAF-6-mediated over-expression of PAI-1 was inhibited by co-expression of wt-CYLD in S. p -infected A549 cells, suggesting that CYLD may target TRAF-6 in inhibiting P[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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It has been shown that the tumor suppressor CYLD targets TRAF6 for deubiquitination to terminate TLR triggered activation of NF-kappaB XREF_BIBR XREF_BIBR.

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The deubiquitinating enzymes A20 and CYLD inhibit NF-kappaB signaling by targeting TRAF6 upstream of IKK, while a recent report shows that CUEDC2 inhibits IKK activity by recruiting a phosphatase PP1 and keeps IKK in an inactivated status.

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It has been demonstrated that the deubiquitinating enzymes A20 and CYLD inhibit NF-kappaB signaling by targeting TRAF6 upstream of IKK, while the deubiquitinating protein DUBA inhibits type I interferon activity by targeting TRAF3.

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18313383

CYLD affects TBK1

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CYLD activates TBK1.

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CYLD activates TBK1. 10 / 10

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Together, these results suggest that CYLD targets TBK1 or its downstream molecules to negatively regulate antiviral response.

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CYLD deficiency causes constitutive activation of TBK1 and IKKε in DCs, and the CYLD-deficient DCs and MEFs are hyper-responsive to VSV in IFNβ induction xref .

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As expected, expression of CYLD resulted in reduction of the ubiquitination levels of overexpressed TBK1, further indicating that CYLD activity targeted TBK1 (XREF_FIG).

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Although this phenotype may involve ubiquitin dependent activation of RIG-I, CYLD also directly targets TBK1 and IKKepsilon to inhibit their ubiquitination 79.

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Genetic deficiency in the DUB CYLD causes constitutive activation of TBK1 and IKKepsilon in DCs, rendering the cells hyperresponsive to VSV induced type I IFN expression XREF_BIBR, XREF_BIBR.

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MIB1/2, Nrdp1, CYLD, A20-TAX1BP1-ABIN1 complex and RNF11-TAX1BP1 complex modulate K63-linked ubquitination of TBK1.

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Because CYLD deficiency causes constitutive activation of IKKε and TBK1, this DUB has been suggested to play an essential role in preventing the aberrant activation of these kinases during the induction of type1 interferon that occurs during viral infection ( xref ).

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CYLD deficiency causes constitutive activation of TBK1 and IKKepsilon in DCs, and the CYLD deficient DCs and MEFs are hyper-responsive to VSV in IFNbeta induction 80.

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CYLD deficiency causes constitutive activation of IKKepsilon and TBK1, which is associated with hyper-induction of IFNs in virus infected cells.

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Because CYLD deficiency causes constitutive activation of IKKepsilon and TBK1, this DUB has been suggested to play an essential role in preventing the aberrant activation of these kinases during the induction of type1 interferon that occurs during viral infection.

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CYLD inhibits TBK1.

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CYLD inhibits TBK1. 7 / 7

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Our previous studies as well as others have demonstrated that A20, TAX1BP1, ABIN1 and CYLD inhibit TBK1 and IKKi by antagonizing their Lys63 linked polyubiquitation XREF_BIBR, XREF_BIBR, XREF_BIBR.

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CYLD also negatively regulates the IKK related kinases, IKKepsilon and TBK1, by the same mechanisms.

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Since we have previously shown that Optn accumulates in the nucleus during the G2/M transition [XREF_BIBR], we speculated that this Optn relocation could prevent Optn and CYLD mediated inhibition of TBK1 activity.

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The effect of CYLD was not specific to RIG-I, as CYLD also deubiquitinated and inhibited the signaling activities of TBK1 and IKKɛ.

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The effect of CYLD was not specific to RIG-I, as CYLD also deubiquitinated and inhibited the signaling activities of TBK1 and IKKepsilon.

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TBK1 signaling was active in these tumors as measured by elevated pCYLD and pTBK1 levels, and, in consonance with our findings in vitro, CYT387 treatment blocked CYLD phosphorylation and paradoxically increased pTBK1 (XREF_FIG).

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The effect of CYLD was not specific to RIG-I, as CYLD also deubiquitinated and inhibited the signaling activities of TBK1 and IKKe.

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CYLD affects JNK

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CYLD inhibits JNK.

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CYLD inhibits JNK. 10 / 10

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Expression of a non cleavable form of CYLD inhibited activation of the JNK pathway and expression of AP-1 target genes in a T-cell line, although CYLD silencing only minimally increased JNK activation [XREF_BIBR], possibly because of redundancy with other deubiquitinating enzymes.

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CYLD, a tumor suppressor and a target gene of NF-κB, negatively regulates NF-κB and JNK activation by removing K63-linked polyubiquitin chains from TRAF2 and TRAF6 as well as several other signaling proteins [214,215].

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The loss of CYLD in both primary T cells and the Jurkat T cell line causes the constitutive activation of Tak1 as well as its downstream targets JNK and IKK.

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On the contrary, CYLD WT overexpression leads to a diminished JNK activation both in non stimulated and in TNF-alpha-stimulated A-CYLD WT cells (XREF_FIG).

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Recent evidence demonstrates that CYLD negatively regulates the c-Jun N-terminal kinase (JNK) signaling pathway, a critical mediator of cell survival.

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Conversely, loss of the K63 specific deubiquitinase CYLD causes spontaneous activation of IKK and JNK as well as their upstream kinase Tak1.

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CYLD negatively regulates the activation of IKK and JNK, and its expression is markedly upregulated under conditions of RANKL induced osteoclastogenesis [XREF_BIBR].

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C-Jun N-terminal kinase (JNK) signaling pathway activated by TNF alpha, anti-CD40 antibody, IL-1 beta, and lipopolysaccharide is repressed by CYLD by reducing the activity of MKK7 and JNKK2, which is [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The tumor suppressor CYLD antagonizes NF-kappaB and JNK signaling by disassembly of Lys63 linked ubiquitin chains synthesized in response to cytokine stimulation.

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Depending on the cellular context CYLD has been shown to negatively regulate NF-kappaB and/or JNK signalling pathways resulting in suppression of cell proliferation and survival.

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CYLD activates JNK.

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CYLD activates JNK. 7 / 7

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2 The inhibition of CYLD function in keratinocytes enhances the activation of the JNK pathway.

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In agreement with the reported negative regulation of JNK and c-Myc activation by CYLD [ xref ], WB analysis of these molecules showed increased Akt, JNK and c-Myc activation (measured as levels of P-Akt, P-JNK and P-c-Myc respectively) in the skin of transgenic mice lacking the DUB function ( xref ).

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In agreement with the reported negative regulation of JNK and c-Myc activation by CYLD [XREF_BIBR], WB analysis of these molecules showed increased Akt, JNK and c-Myc activation (measured as levels of P-Akt, P-JNK and P-c-Myc respectively) in the skin of transgenic mice lacking the DUB function (XREF_FIG).

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Moreover, we found that CYLD m not only increased JNK activity but also increased K63 ubiqutination on both c-Jun and c-Fos, and ultimately potentiated AP1 transcriptional activity.

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Curiously, in CD3+ CD28 stimulated Jurkat T cells, MALT1 cleaves CYLD increasing activation of JNK, but not NF-kappaB [XREF_BIBR].

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In support of this view, MALT1 proteolysis of the inhibitory deubiquitinases A20 and CYLD potentiates NF-kappaB and JNK, respectively [XREF_BIBR, XREF_BIBR], while cleavage of the RNase Regnase-1 prolongs mRNA stability of T cell effector genes [XREF_BIBR].

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CYLD Inhibits Tumorigenesis and Metastasis by Blocking JNK and AP1 Signaling at Multiple Levels.

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CYLD affects TNF

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CYLD activates TNF.

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CYLD activates TNF. 9 / 9

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CYLD Limits Gene Activation and Enhances Cell Death in Response to TNF.

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Hence, the deubiquitinase function of CYLD is required to promote TNF induced programmed necrosis.

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CYLD Promotes TNF-

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CYLD induction mediated, at least in part, the TZD mediated downregulation of tumor necrosis factor alpha (TNFalpha)-induced interleukin 8 (IL-8).

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In addition, CD11c-Cre Cyld (ex7/8 fl/fl) DCs produced more TNF, IL-10, and IL-12 upon infection, which led to enhanced stimulation of IFN-gamma-producing NK cells.

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RNAi mediated silencing of CYLD attenuates ROS production and TNF induced programmed necrosis [XREF_BIBR].

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Moreover, overexpression of CYLD increased TNF-alpha induced cell apoptosis in A549 cells.

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CYLD deficient cells are protected from RIPK1 mediated necroptosis in response to TNF plus caspase inhibition with or without Smac mimetic.

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Consistent with a role in programmed necrosis, CYLD promotes the assembly of the RIP1-FADD-caspase 8 complex in response to TNF, IAP antagonist, and zVAD-fmk treatment [XREF_BIBR].

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CYLD increases the amount of TNF.

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CYLD increases the amount of TNF. 5 / 5

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Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFalpha)-induced mRNA expression of pro inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs).

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Knockdown of CYLD rescued the expression of TNF-alpha and IL-1beta at both the mRNA and protein levels in RBP-J cKO BMDMs (XREF_FIG).

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CYLD inhibits TNF.

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CYLD inhibits TNF. 3 / 3

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OPTN is required for CYLD dependent deubiquitination of RIP and also for CYLD dependent inhibition of TNFalpha induced by NF-kappaB activity.

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The tumor suppressor cylindromatosis (CYLD) inhibits the NF-kappaB pathway by deubiquinating the IKKgamma subunit, as well as TNF receptor associated factor (TRAF) 2, TRAF6, and B-Cell CLL and Lymphoma 3 (BCL3) that are required for maintaining NF-kB activity.

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Concomitant Loss of OTULIN and CYLD Interaction with HOIP Increases M1Ubiquitination at the TNF-RSC and Enhances TNF Induced Gene Activation.

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CYLD affects SMAD3

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CYLD inhibits SMAD3.

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CYLD inhibits SMAD3. 10 / 10

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We thus determined whether GSK3beta is involved in mediating CYLD induced Smad3 degradation.

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Because Akt is known as the major upstream regulator of GSK3beta XREF_BIBR XREF_BIBR, we investigated whether Akt mediates CYLD induced degradation of Smad3.

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Nonetheless, these data suggest that CYLD decreases Smad3 protein stability via negatively regulating Akt.

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These data suggest that CYLD decreases Smad3 stability in a DUB activity dependent manner.

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This interesting result thus led us to determine whether Akt is critically involved in mediating CYLD induced degradation of Smad3 by first examining the effect of Akt knockdown on Smad3 protein stability.

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Interestingly, CYLD decreases Smad3 stability by directly deubiquitinating K63 polyubiquitinated Akt.

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CYLD decreases Smad3 stability via Akt-GSK3beta-CHIP pathway.

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CYLD decreases Smad3 stability by inhibiting Akt.

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On the basis that carboxy terminus of CHIP has been shown to mediate Smad3 degradation XREF_BIBR XREF_BIBR, we first determined whether CHIP mediates CYLD induced Smad3 degradation by using siCHIP.

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Moreover, CYLD decreases Smad3 stability by deubiquitinating K63 polyubiquitinated Akt.

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CYLD activates SMAD3.

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CYLD activates SMAD3. 5 / 5

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To further determine whether CYLD inhibits TGF-beta-signalling by likely targeting Smad3, we next evaluated the effect of CYLD knockdown in Smad3 deficient MEF cells.

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Lim and co-workers showed that CYLD suppresses TGF-beta signalling and prevents lung fibrosis by (indirectly) reducing the stability of Smad3, in an AKT, GSK3beta and E3 ligase carboxy terminus of Hsc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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This study proposes that CYLD inhibits TGFbeta signalling by decreasing the stability of SMAD3 via the AKT-GSK3-CHIP pathway.

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CYLD inhibited transforming growth factor-beta-signalling and prevented lung fibrosis by decreasing the stability of Smad3 in an E3 ligase carboxy terminus of Hsc70 interacting protein dependent manner.

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CYLD inhibits ERK. 10 / 10

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CYLD Impairs Production of Cytokines, ROS, and NO and Reduces Activation of NF-kappaB, ERK1/2, and p38MAPK in Lm Infected BMDM.

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As shown in XREF_FIG, CYLD WT inhibited ERK phosphorylation, while CYLD knockdown, via siCYLD, markedly enhanced ERK activation by NTHi (XREF_FIG).

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However, it remains unknown if CYLD also suppresses ERK activation induced by bacterial pathogens.

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Here we provide clear evidence that CYLD inhibits NTHi induced activation of ERK (XREF_FIG), and we also demonstrate that CYLD controls IL-8 expression via specifically targeting ERK phosphorylation by activating the ERK pathway with a constitutively active form of MEK (XREF_FIG).

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Future studies will focus on using DUB activity deficient CYLD mutant constructs to determine whether DUB activity is essential for the CYLD mediated suppression of ERK signaling pathway induced by bacterial pathogens.

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We next sought to determine how CYLD negatively regulates the ERK signaling pathway in order to mediate NTHi induced IL-8 expression.

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We thus asked whether CYLD inhibited ERK activation.

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In addition, we further investigated the detailed mechanism by which CYLD negatively regulates the ERK signaling pathway in a DUB activity dependent or independent manner.

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CYLD also enhances oxidative stress by inhibiting the activation of the extracellular signal regulated kinase (ERK), p38/AP -1 and c-Myc pathways, ensuring Nrf2 downregulation.

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CYLD activates ERK.

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CYLD activates ERK. 6 / 6

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57 They reported that in human lung A549 cells and lungs of Cyld -/- mice, CYLD targets the activation of ERK.

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However, because Cyld deficiency did not cause the activation of ERK, the target of CYLD might be an intermediate signaling factor specifically mediating the activation of JNK and IKKbeta.

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Here, we examine both human lung epithelial A549 cells and lung of Cyld -/- mice to show that CYLD specifically targets the activation of ERK.

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The finding that CYLD may target the ERK pathway in negatively controlling IL-8 expression is particularly significant.

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Autophagy is an intrinsic defense mechanism against Lm and, therefore, we further investigated whether CYLD-dependent RIPK2 and ERK1/2 activation influences the formation of autophagosomes.

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However, it remained largely unknown whether or how CYLD modulated ERK signaling, when induced by bacterial pathogens.

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E6 affects CYLD

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E6 activates CYLD.

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E6 activates CYLD. 9 / 9

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For example, the E6 protein of human papillomavirus (HPV) targets CYLD for ubiquitination and proteasomal degradation, leading to persistent NF-kappaB activation by hypoxia in HPV infected cancer cells 130.

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Under hypoxic conditions, the HPV encoded E6 protein inactivates the CYLD tumor suppressor, a negative regulator of the NF-kappaB pathway and thereby allows for unrestricted activation of NF-kappaB.

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Interestingly, there is a precedent for E6 influencing signaling pathways involving K63 branching : HPV E6 targets the lysine 63 specific Deubiquitinase CYLD (a negative regulator of the NF-kB pathway), thereby causing prolongation of hypoxia induced NF-kB activation.

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Therefore, E6 targeting of CYLD appears to be an essential step in HPV mediated tumorigenesis.

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One study demonstrated that Cyld is targeted for degradation by HPV (human papillomavirus) E6 virus, to prolong NF-kappaB activation following hypoxia [XREF_BIBR].

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Under hypoxic conditions, high-risk E6 also inactivates the CYLD tumor suppressor through interactions with CYLD deubiquitinase to allow unrestricted activation of NF-kappaB XREF_BIBR.

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9 In cancers related to human papillomavirus (HPV), such as cervical cancer, CYLD is targeted by HPV E6 protein for degradation.

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For these studies, we studied the state of CYLD ubiquitination in SiHa and HeLa cells that were treated with E6 specific siRNA or control siRNA.

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Based on these results, we concluded that E6 targets CYLD for proteasome mediated degradation.

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E6 inhibits CYLD.

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E6 inhibits CYLD. 4 / 4

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In preclinical models, under hypoxic conditions, the HPV encoded E6 protein promotes inactivation and degradation of the CYLD tumor suppressor, resulting in prolonged activation of NF-kappaB pathway [XREF_BIBR].

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As HPV16 E6 inactivates CYLD XREF_BIBR and because defective CYLD causes enhanced nuclear import of BCL-3, we reasoned that HPV16 E6 may induce KIAA1199 expression through BCL-3 in transformed keratinocytes.

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It is also plausible that post-translational hydroxylation may take place on a protein involved in formation of a protein complex that includes E6 and CYLD, whereby hydroxylation impairs complex formation and, by extension, the ability of E6 to target CYLD for ubiquitination.

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Importantly, degradation of CYLD by E6 was prevented by treatment of cells with the proteasome inhibitor, MG132 (XREF_FIG).

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E6 decreases the amount of CYLD.

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E6 decreases the amount of CYLD. 3 / 3

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Transient transfection studies involving E6 and Flag tagged CYLD constructs in HEK293 cells demonstrated that CYLD expression was reduced by E6 in a dose dependent manner (XREF_FIG).

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E6 reduces CYLD expression through a proteasome dependent mechanism.

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Thus, in ambient oxygen tension, E6 gene silencing in HPV positive cells led to NF-kappaB and IKKbeta activation and increased CYLD expression, whereas ectopic expression of E6 in HPV negative cells resulted in NF-kappaB activation and CYLD degradation.

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CYLD affects necroptotic process

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CYLD activates necroptotic process.

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CYLD activates necroptotic process. 10 / 10

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CYLD is required for TLR3 or TLR4 receptor induced necroptosis.

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The deubiquitinase CYLD has been identified to be involved in TLR induced necroptosis in macrophages from wild derived MOLF mice.

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CYLD deficient cells are protected from RIPK1 mediated necroptosis in response to TNF plus caspase inhibition with or without Smac mimetic.

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We found that inhibition of cyld expression in Jurkat cells also attenuated necroptosis (XREF_FIG).

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Active caspase 8 in Complex IIa not only initiates the caspase cascade and the apoptotic program, but also cleaves and inactivates essential necroptosis mediators such as RIPK1, RIPK3 and CYLD.

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10 Active Caspase-8 not only initiates the apoptotic program but also cleaves and inactivates essential necroptosis mediators such as RIPK1, RIPK3 and CYLD.

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Knockdown of the RNA sensing molecule RIG-I or the RIP1 deubiquitin protein, CYLD, but not STING, rescued cells from SeV induced necroptosis.

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Specifically, CYLD removed lysine 63 and linear ubiquitin chains from RIP1 and promoted necroptosis in TNF receptor signaling, which was involved in the regulation of different cellular processes including inflammation, fibrosis, and cancer.

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However, loss of CYLD in vivo was shown to delay, but not prevent necroptosis during skin inflammation [XREF_BIBR].

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It has previously been shown that knockout of lysine 63 deubiquitinase CYLD significantly inhibits necroptosis in other cell lines, and serum response factor (SRF) could regulate CYLD gene expression through p38 mitogen activated protein kinase (p38 MAPK).

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CYLD inhibits necroptotic process.

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Recently, CYLD was shown to negatively regulate necroptosis induced by oxygen-glucose-deprivation (OGD) in primary cortical neurons.

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The inhibition of cIAP and activation of CYLD could also promote necroptosis XREF_BIBR, XREF_BIBR.

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Caspase-8 also targets the deubquitinase CYLD preventing RIPK1 initiation of necroptosis [XREF_BIBR, XREF_BIBR].

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In apoptotic signaling, caspase-8 may cleave de-ubiquitinase CYLD, RIP1 and RIP3, blocking initiation of necroptosis.

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Thus, in the case of KP35 infection, induction of necroptosis is not due to increased CYLD, but rather the previously observed inhibition of necroptosis by CYLD was not detected.

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CYLD affects cell death

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CYLD activates cell death.

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CYLD activates cell death. 10 / 10

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Genetic manipulation of Cyld in combination with pharmacological modulation of autophagic functional status revealed that CYLD suppressed autolysosomal degradation and promoted cell death in cardiomyocytes.

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21 Previously, it was reported that CYLD promotes induction of cell death by TNF-alpha.

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XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR In cell death assays, overexpression of CYLD significantly enhanced induction of cell death stimulated by TNF-alpha, but this effect was abolished in CLIPR-59 knock-down cells (XREF_FIG).

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CYLD Limits Gene Activation and Enhances Cell Death in Response to TNF.

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In control non targeting siRNA transfected cells, the treatment with TNFalpha induced at least 60-70% cell death, which is blocked by knockdown of cyld and tnfr1 but not by that of rip1 (XREF_FIG).

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We have detected that overexpression of CYLD contributed to cell death of the lung cancer cells.

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Firstly, we asked whether overexpression of CYLD-flag could induce cell apoptosis, which probably contributed to CYLD induced cell death.

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Cell death initiated by TNF in Cyld -/- MEFs expressing CYLD-D215A was blocked by the RIPK1 inhibitor Necrostatin-1 17 (XREF_FIG, compare panel 6 and panel 7), or by specific knockdown of Ripk1 or Ripk3 (XREF_FIG), demonstrating that RIPK1 and RIPK3 are downstream of CYLD.

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Increasing CYLD promotes apoptosis and increasing PNUTL enhances cell death via TGF.

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CYLD inhibits cell death.

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CYLD inhibits cell death. 4 / 4

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Consistent with the data above, silencing CYLD largely abolished caspase 8 activation and necroptotic cell death induced by 5z-7 plus TNFalpha (XREF_FIG).

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Ablation of the RIP1 deubiquitinase CYLD largely blocked apoptotic and necroptotic cell death induced by TAK1 inhibition.

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SMAC mimetics can similarly disrupt CYLD phosphorylation and lead to ATLL cell death through reduction of RIPK1 ubiquitination, which is CYLD dependent.

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However, prolonged ATRA treatment reduced CYLD SUMOylation and promoted cell death instead.

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Modified mutated CYLD inhibits cell death. 1 / 1

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Overexpression of non SUMOylatable mutant CYLD in neuroblastoma cells reduced retinoic acid induced NF-kappaB activation and differentiation of cells, but instead promoted cell death.

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CYLD affects DDX58

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CYLD inhibits DDX58.

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CYLD inhibits DDX58. 6 / 6

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Conversely, the removal of Lys63 linked ubiquitylation by the cellular deubiquitylating enzymes (DUBs) ubiquitin C-terminal hydrolase 3 (USP3), USP21 and CYLD, represses RIG-I signalling.

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The tumor suppressor CYLD (cylindromatosis), another OTU de-ubiquitinating enzyme that removes Lys 63 linked polyubiquitin chains, was also recently shown to negatively regulate RIG-I.

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USP3, USP21 and CYLD inhibit RIG-I K63-linked ubiquitination and activation.

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For example, the 3C protein of enterovirus 71 (EV71), a member of the Picornaviridae family that causes hand, foot and mouth disease, and occasionally severe central nervous system diseases, downregulates the host microRNA miR-526a to increase the expression of the cellular DUB enzyme CYLD, thus inhibiting the activation of RIG-I 74.

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Conversely, the removal of Lys63-linked ubiquitylation by the cellular deubiquitylating enzymes (DUBs) ubiquitin C-terminal hydrolase 3 (USP3), USP21 and CYLD, represses RIG-I signalling (reviewed in REF.

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Another ubiquitin ligase RNF135 (also known as Riplet) is similarly involved in the positive regulation of RIG-I signaling, while RNF125 and the deubiquitinase CYLD are known to negatively regulate RIG-I signaling.

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CYLD bound to DDX58 inhibits DDX58. 2 / 2

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CYLD binds to RIG1 and thereby inhibits ubiquitylation and signalling functions of RIG1.

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CYLD binds to RIG-I and inhibits the ubiquitination and signaling function of RIG-I XREF_BIBR, XREF_BIBR.

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CYLD inhibits ubiquitinated DDX58. 1 / 1

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Loss of CYLD in DCs causes accumulation of ubiquitinated RIG-I.

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CYLD activates DDX58.

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CYLD activates DDX58. 5 / 5

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Ubiquitylation events are reversible processes, and, accordingly, several deubiquitylating enzymes, in particular ubiquitin specific peptidase 3 (USP3), USP21 and CYLD lysine 63 deubiquitinase (CYLD), modulate RIG-I signalling by removing K63-polyubiquitin chains, although with unique kinetics.

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The effect of CYLD was not specific to RIG-I , as CYLD also deubiquitinated and inhibited the signaling activities of TBK1 and IKKepsilon .

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Ubiquitylation events are reversible processes , and , accordingly , severaldeubiquitylating enzymes , in particular ubiquitin specific peptidase 3 ( USP3 ) , USP21 and CYLD lysine 63 deubiquitinase ( CYLD ) , modulate RIG-I signalling by removing K63-polyubiquitin chains , although with unique kinetics ( reviewed elsewhere112 ,118 ) .

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The data indicate that CYLD targets RIG-I as well as TBK1 for deubiquitination that leads to inactivation of the signaling.

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miR-526a downregulates the expression of the deubiquitylating enzyme CYLD, which ultimately promotes RIG-I K63 linked ubiquitylation and interferon responses 152.

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CYLD increases the amount of DDX58.

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CYLD increases the amount of DDX58. 1 / 1

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CYLD silencing resulted in an increase of poly IC induced RIG-I and MDA5 protein levels and increased CCL5 and CXCL10 mRNA and protein expression, but unexpectedly decreased mRNA expressions of RIG-I and MDA5.

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MALT1 affects CYLD

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MALT1 inhibits CYLD.

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MALT1 inhibits CYLD. 8 / 8

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Human paracaspase MALT1 is central to plasticity of lymphocytes as MALT1 proteolytic inactivation of CYLD ensures sustained activation of NFκB as well as RIG1 for providing innate immune response ( Be[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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T-cell receptor induced JNK activation requires proteolytic inactivation of CYLD by MALT1.

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CYLD but Not RelB Nor Regnase-1 Is Reduced by MALT1 Activity in Macrophages.

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In summary, our study demonstrates for the first time that (i) MALT1 modulates TLR7 agonist- and IAV induced MMP-9 response in alveolar macrophages; (ii) MALT1 mediates CYLD reduction in macrophages upon TLR7 stimulation; (iii) MMP-9 production in alveolar macrophages is through NF-kappaB but not AP-1; and that (iv) MALT1 deficiency results in reduced IAV induced disease severity.

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Human paracaspase MALT1 is central to plasticity of lymphocytes as MALT1 proteolytic inactivation of CYLD ensures sustained activation of NFkappaB as well as RIG1 for providing innate immune response [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Inhibition of MALT1 activity by z-VRPR-fmk reversed CYLD degradation slightly but the difference did not reach statistical significance.

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Here, we show that T-cell receptors (TCR) activation, as well as overexpression of the oncogenic API2-MALT1 fusion protein, results in proteolytic inactivation of CYLD by MALT1, which is specifically required for c-jun N-terminal kinase (JNK) activation and the inducible expression of a subset of genes.

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MALT1 activates CYLD.

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MALT1 activates CYLD. 5 / 5

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At the same time, MALT1 could function as a protease activity upon TCR and CD28 co-stimulation to inactivate negative regulators of NF-kappaB signaling such as the A20 (also known as TNFAIP3), CYLD (cylindromatosis), RNase Regnase-1 as well as RelB and HOIL1 [XREF_BIBR - XREF_BIBR].

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The requirement for MALT1 mediated CYLD cleavage for intact JNK signaling downstream of the TCR has been previously described XREF_BIBR.

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JNK activation has been connected to MALT1 catalysed CYLD cleavage XREF_BIBR.

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In addition, MALT1 promotes lymphocyte activation by cleaving A20 and CYLD, deubiquitinating enzymes that have inhibitory roles in the NF-kappaB and JNK pathway, respectively XREF_BIBR, XREF_BIBR, and by cleavage of BCL10, which promotes lymphocyte adhesion XREF_BIBR.

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To further confirm that MALT1 protease mediated the cleavage of MCPIP1 in macrophages, we used siRNA to knockdown MALT1 expression in macrophages, confirming that MALT1 promoted MCPIP1, but not A20, CYLD, BCL10 or RelB, degradation.

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MALT1 decreases the amount of CYLD.

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MALT1 decreases the amount of CYLD. 1 / 1

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Our results indicate that MALT1 activation by either imiquimod or IAV reduces the levels of CYLD and that imiquimod induced reduction is MALT1 activity dependent.

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CYLD affects Ubiquitin

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CYLD inhibits Ubiquitin.

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CYLD inhibits Ubiquitin. 9 / 9

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We further show that CYLD negatively regulates a ubiquitin dependent NF-kappaB activator, RIP1.

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This suppression of CYLD promoted ubiquitin conjugation of NF-kappaB signaling pathway components and induction of an aggressive phenotype of glioma cells both in vitro and in vivo.

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Consistent with the notion that NF-kappaB signalling could be turned off through negative feedback mechanism involving CYLD mediated ubiquitin (Ub) deconjugation [XREF_BIBR], the CYLD depletion compromised and CYLD overexpression potentiated cell apoptosis are separately overrided by NF-kappaB inhibitor BAY 11-7085 and IkappaBalpha siRNA.

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Mechanistically, CYLD removes lysine-63-linked ubiquitin chains from TRAF2, TRAF6, and NEMO, whereas lysine-48-linked ubiquitin chains are not degraded by CYLD.

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CYLD was shown to negatively regulate NF-kappaB and MAPK activation by removing ubiquitin chains from key signalling molecules including NEMO, TRAF2, TRAF6 and RIPK1.

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CYLD and TNFAIP3 and A20 negatively regulate the NFkappaB pathway by removing ubiquitin chains from multiple signaling molecules including TRAFs and RIP.

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XREF_BIBR Suppression of CYLD by miR-182 promoted ubiquitin conjugation of NFkappaB signaling components and led to sustained NFkappaB activation.

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Deubiquitinating enzyme CYLD negatively regulates the ubiquitin dependent kinase Tak1 and prevents abnormal T cell responses.

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CYLD activates Ubiquitin.

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CYLD activates Ubiquitin. 4 / 4

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MiR-182 can suppress cylindromatosis (CYLD), a deubiquitinase that mediates ubiquitin deconjugation and acts as an inhibitor of nuclear factor kappaB (NF-kappaB) activation, leading to overactivation of NF-kappaB signaling.

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Both CYLD and TRAF2 phosphorylation thus increase ubiquitin-dependent NF-κB signaling.

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Thus, CYLD mediated removal of ubiquitin chains, including of linear chains, from components of the TNF-RSC results in diminished TNF induced gene activation and, at the same time, enhanced cell death.

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CYLD affects AKT

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CYLD inhibits AKT.

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CYLD inhibits AKT. 9 / 9

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Overexpression of CYLD, a DUB for K63 linked ubiquitination of AKT, decreases AKT activity mediated by TRAF6 [XREF_BIBR].

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Thus, we next explored the possibility that CYLD may inhibit Akt mediated fibrotic response via deubiquitinating TRAF6.

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To further determine how CYLD negatively regulates Akt, we first examined whether CYLD physically interacts with Akt by performing co-immunoprecipitation experiments.

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Furthermore, the results indicated that CRAL mainly resided in the cytoplasm and could sponge endogenous miR-505 to upregulate cylindromatosis (CYLD) expression, which further suppressed AKT activation and led to an increase in the sensitivity of gastric cancer cells to cisplatin in vitro and in preclinical models.

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These results suggest that CYLD suppresses Akt activation to inhibit prostate cancer cells growth and development.

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Nonetheless, these data demonstrate that CYLD indeed inhibits Akt mediated fibrotic response by at least in part directly interacting with and deubiquitinating Akt.

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It is possible that CYLD may inhibit Akt mediated fibrotic response by actually deubiquitinating TRAF6.

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Taken together, these data provide strong evidence that CYLD negatively regulates Akt by directly interacting with and deubiquitinating K63 polyubiquitinated Akt, both in vitro in a cell-free system and in vivo under endogenous condition.

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CYLD activates AKT.

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CYLD activates AKT. 4 / 4

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To determine whether CYLD inhibits cell proliferation and survival by suppressing activation of Akt, we performed cell proliferation and apoptosis assays on control and CYLD-knockdown prostate cancer cells treated with or without the PI3K inhibitors LY294002 or wortmannin.

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CYLD decreases Smad3 stability by inhibiting Akt.

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Together, these data suggest that CYLD decreases Smad3 stability and TGF-beta-signalling by inhibiting Akt.

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CYLD affects RIPK1

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CYLD activates RIPK1.

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CYLD activates RIPK1. 7 / 7

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Then, we found that RIP3 accounts for shikonin induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3.

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CYLD destabilizes complex I and allows RIP1 to dissociate from the plasma membrane.

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In addition we show that optineurin is required for CYLD mediated deubiquitnation of RIP.

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Rather than inhibiting RipK1 degradation, knock-down of CYLD and/or A20 appeared to enhance the degradation of RipK1, suggesting that CYLD and A20 promote maintenance of RipK1.

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CYLD and A20 function as deubiquitination enzymes to inhibit IKK by targeting RIP1 upstream of IKK, while CUEDC2 acts as an adaptor protein to keep IKK in an inactivated status by recruiting a phospha[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Mouse RIP3, RIP1, MLKL, and CYLD siRNAs were synthesized by GenePharma : RIP3-1 (cccgacgaugucuucugucaa), RIP3-2 (cuccuuaaagucaauaaacau), RIP1-1 (ccacuagucugacugauga), RIP1-2 (ucaccaauguugcaggaua), CYLD-1 (uccauugaggauguaaauaaa), CYLD-2 (aaggguugaaccauuguuaaa), MLKL-1 (gagauccaguucaacgaua), and MLKL-2 (uaccaucaaaguauucaacaa).

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CYLD inhibits RIPK1.

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CYLD inhibits RIPK1. 5 / 5

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Then, we found that RIP3 accounts for shikonin induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3.

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In support, overexpression of Snail1 reduced CYLD expression and upregulated RIP1 in Mel-CV.

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Caspase-8 also targets the deubquitinase CYLD preventing RIPK1 initiation of necroptosis [XREF_BIBR, XREF_BIBR].

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Formation of the secondary, receptor-free cytoplasmic complex II is largely dependent on the activity of DUBs, specifically cylindromatosis (CYLD), A20 (also known as TNFAIP3) and ubiquitin thioesterase OTULIN, which destabilize complex I, abrogate NF-kappaB activation and release RIPK1 from complex I, which then forms the cytosolic complex II XREF_BIBR, XREF_BIBR.

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Rather than inhibiting RipK1 degradation, knock-down of CYLD and/or A20 appeared to enhance the degradation of RipK1, suggesting that CYLD and A20 promote maintenance of RipK1.

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CYLD increases the amount of RIPK1.

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CYLD increases the amount of RIPK1. 1 / 1

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Furthermore, we demonstrate FMRP to be critically important for regulating key molecules in TNF receptor 1 (TNFR1)-dependent apoptosis and necroptosis including CYLD, c-FLIP S and JNK, which contribute to prolonged RIPK1 expression.

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CYLD affects SERPINE1

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CYLD decreases the amount of SERPINE1.

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CYLD decreases the amount of SERPINE1. 9 / 9

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Together, these results indicate that TRAF-6 mediates S.p-induced PAI-1 expression, and CYLD inhibits PAI-1 expression probably through deubiquitinating TRAF-6.

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CYLD was suggested to interfere with the NFAT signalling pathway by deubiquitylating transforming growth factor-β-activated kinase 1 (TAK1), and to negatively regulate KK3-p38 kinase-dependent expression of plasminogen activator inhibitor-1 [39], [40].

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The authors showed that CYLD inhibited S. p -induced PAI-1 expression in lung, thereby potentiating pulmonary damages [18].

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In this study, we provided evidence to show that CYLD inhibits PAI-1 expression probably through directly interacting with and deubiquitinating TRAF-6.

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In this issue of Immunity, Lim et al. (2007) demonstrate that CYLD, a deubiquinating enzyme, represses the expression of plasminogen activator inhibitor-1, which is critical in preventing tissue damage.

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Results from the same study using the CYLD knockout cells have showed that CYLD negatively regulates PAI-1 expression via inhibition of MKK3-p38 MAPK signaling pathway [18].

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Cylindromatosis (CYLD) inhibits Streptococcus pneumonia induced plasminogen activator inhibitor-1 expression via interacting with TRAF-6.

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Our evidences here demonstrated that CYLD inhibited S. p -stimulated PAI-1 expression.

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Based on these information, we propose that CYLD associates, deubiquinites and in-activates TRAF-6, thus inhibiting subsequent PAI-1 expression.

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Modified CYLD decreases the amount of SERPINE1. 1 / 1

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Over-expression of wt-CYLD dramatically inhibited PAI-1 mRNA expression in A549 cells with S. p infection.

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CYLD inhibits SERPINE1.

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CYLD inhibits SERPINE1. 2 / 2

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Since PAI-1 inhibits plasminogen production and fibrinolysis, the indirect inhibition of PAI-1 by CYLD in combination with reduced lung hemorrhage and increased PAI-1 production of Cyld -/- mice indicate that CYLD caused augmented fibrinolysis.

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Since PAI-1 inhibits plasminogen production and fibrinolysis, the indirect inhibition of PAI-1 by CYLD in combination with reduced lung hemorrhage and increased PAI-1 production of Cyld −/− mice indicate that CYLD caused augmented fibrinolysis.

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CYLD activates SERPINE1.

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CYLD activates SERPINE1. 1 / 1

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Interestingly, CYLD deficiency in the Cyld deficient mouse results in excessive production of PAI-1, thus providing efficient protection against lethality XREF_BIBR.

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SNAI1 affects CYLD

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SNAI1 decreases the amount of CYLD.

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SNAI1 decreases the amount of CYLD. 6 / 6

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Snail can inhibit CYLD expression in melanoma [XREF_BIBR].

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CYLD expression is downregulated by the transcriptional repressor Snail in both basal cell carcinoma and melanoma.

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Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma.

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Snail also promotes proliferation in a melanoma model by repressing expression of CYLD, a tumor suppressor gene that functions as a deubiquitination enzyme.

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Reduced CYLD expression in basal cell carcinoma was mediated by GLI1 dependent activation of the transcriptional repressor Snail.

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However, CYLD mRNA transcription is directly inhibited by Snail [XREF_BIBR] and the Notch target Hes1 [XREF_BIBR], both of which are up-regulated and activated under hypoxic conditions [XREF_BIBR, XREF_BIBR].

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Now, Massoumi et al. show that Snail also promotes tumor cell division by shutting off the tumor suppressor CYLD.

| PMC

SNAI1 increases the amount of CYLD.

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SNAI1 increases the amount of CYLD. 1 / 1

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Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma.

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CYLD affects necrotic cell death

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CYLD activates necrotic cell death.

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CYLD activates necrotic cell death. 10 / 10

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They inhibit programmed necrosis by cleavage and inactivation of essential necrosis mediators including RIP1, RIP3 and CYLD [XREF_BIBR - XREF_BIBR].

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Overexpression of CYLD Enhances TNF-alpha-Induced Cell Necrosis of Lung Cancer Cells.

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In addition, knockdown of CYLD, a deubiquitinase of RIP1, blocked TNF-alpha-induced necrosis of HT-22 cells.

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Hence, CYLD was thought to promote necrosis by de-ubiquitination of RIP1 at the TNFR-1 membrane complex.

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Inhibition of CYLD expression inhibits TNF-alpha-induced Jurkat cell program necrosis, indicating that CYLD is a critical regulator of procedural necrosis.

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When Caspase 8 activity was inhibited, L929 cells died by necrosis, which was blocked by knockdown of either CYLD or RIPK3 (XREF_SUPPLEMENTARY).

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In support of caspase 8 's role in necrosis, cleavage resistant mutants of RIP1, RIP3 and CYLD promote necrosis without an obligate need to inhibit caspases.

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All of the data revealed that overexpression of CYLD promoted cell necrosis in lung cancer cells.

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22 Therefore, we propose that CYLD protein levels decrease to evade the necrosis elicited by sustained high CYLD levels.

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We found that expression of GFP tagged wild type CYLD, but not the deubiquitinase inactive mutant C601S, enhanced TNF induced programmed necrosis in CYLD -/- MEFs (XREF_FIG).

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CYLD inhibits necrotic cell death.

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CYLD inhibits necrotic cell death. 2 / 2

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Interestingly, CYLD protein levels decreased in late-phase apoptosis, despite consistently upregulated mRNA levels (XREF_FIG), likely due to CYLD cleavage by caspase-8 to prevent necrosis.

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22 Therefore, we propose that CYLD protein levels decrease to evade the necrosis elicited by sustained high CYLD levels.

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CYLD affects Neoplasm Invasiveness

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CYLD inhibits Neoplasm Invasiveness.

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CYLD inhibits Neoplasm Invasiveness. 10 / 10

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Histologically, CYLD clearly prevented massive immune cell infiltration surrounding necrotic regions, and pseudopalisades appeared in bevacizumab treated control tumors.

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For example, inhibition of CYLD expression enhanced human malignant melanoma growth and invasion [XREF_BIBR].

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Together, these findings suggest that CYLD restricts infiltration of inflammatory cells and invasion enhanced by increased hypoxia after anti-VEGF therapy in GBM.

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Furthermore, CYLD overexpression inhibited SMAD7 mediated cell invasion, while CYLD depletion increased SMAD7 mediated cell invasion in OSCC cells.

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These findings suggest that CYLD inhibits NPC development and provides strong evidence supporting a role for CYLD inhibiting fibroblast and endothelial stromal cell infiltration into NPC via suppressing the NF-kB pathway.

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These clinical findings support a link between the known tumor promoter Snail1 and its transcriptional target CYLD, indicating an important role for Snail1 to suppress CYLD during progression of melanoma and for CYLD to suppress melanoma cell proliferation and invasion.

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Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo.

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Additionally, CYLD was able to inhibit fibroblast and endothelial stromal cell infiltration into the NPC tumor microenvironment.

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Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma.

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Treatment with sorafenib, EAC and sorafenib/EAC inhibited cell invasion by 57.0%, 67.5% and 86.4%, respectively (Fig. xref ).

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CYLD activates Neoplasm Invasiveness.

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CYLD activates Neoplasm Invasiveness. 2 / 2

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These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells.

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Furthermore, CYLD overexpression inhibited SMAD7 mediated cell invasion, while CYLD depletion increased SMAD7 mediated cell invasion in OSCC cells.

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CYLD affects Interferon

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CYLD inhibits Interferon.

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CYLD inhibits Interferon. 7 / 7

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However , as viral infection goes on , CYLD accumulates and cleaves the K63-linked ubiquitin chains of RIG-I , inhibiting virus-triggered type I IFN signaling .

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Ectopic expression of CYLD antagonizes the IFN response whereas siRNA-mediated knockdown of CYLD expression allows for a more robust IFN response.

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Several DUBs were shown to have an inhibitory effect on the RIG-I signalling pathway (Fig XREF_FIG), as for example knockdown of CYLD enhanced type-I IFN production in response to SeV infection whereas ectopic CYLD expression inhibited it XREF_BIBR.

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Since CYLD negatively regulates IFN induction, XREF_BIBR, XREF_BIBR we examined whether the loss of CYLD renders mice more resistant to viral infection.

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Ectopic expression of CYLD inhibits the IRF3 signalling pathway and IFN production triggered by RIG-I; conversely, CYLD knockdown enhances the response.

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The deubiquitinating enzyme CYLD cleaves K63 linked polyubiquitin chains from specific substrates, including tumor necrosis factor receptor associated factors (TRAF)-2, TRAF6, transforming growth factor beta activated kinase 1 (TAK1), B cell lymphoma 3 (BCL3), STAT3, nuclear factor kappa B essential modulator (NEMO), and retinoic acid inducible gene 1 (RIG-1), and negatively regulates the activation of NF-kappaB, MAPKs, and type I IFN production.

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Strikingly, the CYLD and TRAF3 genetic alterations affected mutually exclusive HPV+ HNSCC tumor groups, suggesting that alterations in either TRAF3 or CYLD may function independently and sufficiently to deregulate the downstream NF-kappaB and IFN responses.

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CYLD activates Interferon.

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CYLD activates Interferon. 5 / 5

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Release of the CYLD mediated inhibition of TBK1 during this phase results in enhanced IFN and ISG signaling pathway, independently of viral infection.

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For example, the DUB enzyme cylindromatosis (CYLD) was shown to directly bind RIG-I and mediate the removal of K63-ub and limit IFN induction [XREF_BIBR].

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It was initially believed that CYLD inhibited IFN signaling by deubiquitinating the PRR, RIG-1, and downstream kinases TANK binding kinase 1 (TBK-1) and inhibitor of NF-kappaB kinase Epsilon (IKKEpsilon) 44; but, surprisingly, IFN response to vesicular stomatitis virus in CYLD knockout mice or cells from these mice was abrogated.45 On the basis of these reports, TRAF3 and CYLD may serve similar functions after viral infection, namely, to inhibit NF-kappaB and activate IFN.

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For example, the DUB enzyme cylindromatosis (CYLD) was shown to directly bind RIG-I and mediate the removal of K63-ub and limit IFN induction [45].

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Based on these reports, TRAF3 and CYLD may serve similar functions after viral infection, namely to inhibit NF-kappaB and activate IFN.

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CYLD affects Cell Survival

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CYLD inhibits Cell Survival.

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CYLD inhibits Cell Survival. 7 / 7

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Overexpressed CYLD also significantly inhibited cell viability.

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In T cell acute lymphoblastic leukemia (T-ALL), CYLD expression is repressed by the Notch and Hes1 pathway to promote persistent IKK activation and cell survival [XREF_BIBR].

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The results indicated that cell viability of Huh-7 and HepG2 cells was inhibited by EAC and EACG (Figures xref ).

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In various tumor types, CYLD loss can lead to cell survival or cell proliferation.

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Loss of CYLD in different types of tumors leads to either cell survival or proliferation.

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Reduced expression of CYLD promotes cell survival and inflammation in gefitinib treated NSCLC PC-9 cells : targeting CYLD may be beneficial for acquired resistance to gefitinib therapy.

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Furthermore, cell viability assessed by MTS assay was also suppressed by overexpressed CYLD (20% inhibition; P < 0.05, compared with control), but not by catalytically inactive CYLD.

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CYLD activates Cell Survival.

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CYLD activates Cell Survival. 5 / 5

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CYLD is among the most frequently mutated genes in multiple myeloma and likely contributes to the persistent NF-kappaB activation and enhanced cell survival in these tumors.

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The decrease in cell viability caused by CYLD knockdown was due to induction of apoptosis, as it was associated with activation of the caspase cascade and was abolished by treatment with a general caspase inhibitor.

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Downregulation of CYLD promoted cell survival and migratory activities through NF-kappaB activation, whereas CYLD overexpression inhibited those activities in MDA-MB-231 cells.

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miR-19a is a member of the miR-17-92 cluster and has been shown to be overexpressed in T-cell acute lymphoblastic leukemia and multiple myeloma where it was revealed that miR-19a negatively regulates the expression of CYLD and SOCS-1 respectively to promote cell survival and pathogenesis [XREF_BIBR, XREF_BIBR].

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CYLD deficiency promotes cancer cell proliferation, cell survival and tumorigenesis.

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CYLD affects cell differentiation

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CYLD activates cell differentiation.

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CYLD activates cell differentiation. 9 / 9

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Increased CYLD expression enhances the differentiation of keratinocytes in human skin equivalents.

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Importantly, we have discovered that CYLD WT also promotes the differentiation of A431 tumoral keratinocytes through inhibition of JNK activation.

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The decreased JNK pathway activation in the H-CYLD WT cells appears as a plausible mechanism for CYLD induction of keratinocytes differentiation.

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We show that CYLD overexpression increases keratinocyte differentiation while CYLD loss of function impairs epidermal differentiation.

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Furthermore, depletion of beta-TRCP induced CYLD accumulation and TRAF6 deubiquitination in osteoclast precursor cells, leading to suppression of RANKL induced osteoclast differentiation.

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As a result, we have found that forced expression of wild-type CYLD (CYLD WT) both in HaCaT keratinocytes and in the skin equivalents enhances keratinocyte differentiation, while the inhibition of CYLD function by expression of a catalytically inactive form of CYLD impairs epidermal differentiation.

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In addition to the skin appendages changes, the K5-CYLD C/S mice show epidermal alterations, mainly impaired keratinocyte differentiation, thus confirming in vivo the results that our group have previously described using a model of skin equivalents of human HaCaT keratinocytes [XREF_BIBR], in which we demonstrated that the overexpression of the wild-type CYLD (CYLD wt) promoted keratinocyte differentiation, whereas the expression of the mutant CYLD C/S prevented, through the activation of the JNK pathway, the epidermal differentiation [XREF_BIBR].

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CYLD inhibits proliferation and metastasis of melanoma cells in vivo.

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Functional assays revealed CYLD inhibits NPC cell proliferation and migration in vitro and suppresses NPC tumorigenicity and metastasis in vivo by negatively regulating the NF-kB signaling pathway.

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In summary, these data show that reduced CYLD expression induces tumorigenicity of melanoma, and that reexpression of CYLD reduces their tumor growth and metastasis in vivo.

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CYLD Inhibits Tumorigenesis and Metastasis by Blocking JNK and AP1 Signaling at Multiple Levels.

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Functional assays revealed CYLD inhibits NPC cell proliferation and migration in vitro and suppresses NPC tumorigenicity and metastasis in vivo by negatively regulating the NF-kB signaling pathway .

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Based on our results, loss of CYLD positively affects the formation of lymph vessels in melanoma and enhances metastasis, supporting the important role of CYLD especially in the early process of melanoma progression.

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This mechanism plays an important role for the growth of melanoma cells because stable expression of CYLD in melanoma cells reduced tumor growth and metastasis in vivo in a xenograft model.

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Modified CYLD inhibits Neoplasm Metastasis. 1 / 1

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Re-expression of CYLD in melanoma cells with constitutively high Snail1 levels inhibited N-cadherin expression, leading to a reduced migratory and invasive potential in vitro and less pulmonary metastasis in a murine in vivo model.

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CYLD activates Neoplasm Metastasis.

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CYLD activates Neoplasm Metastasis. 4 / 4

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It has been recently suggested that CYLD down-regulation could increase breast cancer metastasis through NFkappaB activation.

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Hayashi et al. have found that CYLD downregulation promoted breast cancer metastasis via NF-kappaB activation, including RANKL signaling [XREF_BIBR].

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In conclusion, PCDH-gamma-A12 and SLC19A1 promoters, but not CREB and CYLD promoters, are hypermethylated and contribute to the occurrence and metastasis of colorectal cancer.

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CYLD downregulation may promote breast cancer metastasis via NF-kappaB activation, including RANKL signaling.

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Glu-Ala affects CYLD

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Glu-Ala increases the amount of CYLD.

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Glu-Ala increases the amount of CYLD. 6 / 6

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We have also demonstrated that EA induced both apoptosis and necroptosis in CLL cells by inhibiting LEF1 function and restoring CYLD expression.

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EA interfered with LEF1 binding to DNA and restored CYLD expression.

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CYLD expression was increased by EA so we speculate that the negative feedback may control CYLD activity over time and this may inhibit excessive regulation.

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Interestingly, we found that EA enhanced CYLD expression in all 6 samples.

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Thus, EA upregulated expression of CYLD in peri-ischemic areas after focal cerebral ischemia and reperfusion.

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Thus, we hypothesized that EA would enhance CYLD expressions by restricting LEF1 function.

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Glu-Ala activates CYLD.

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Glu-Ala activates CYLD. 3 / 3

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In addition, EA increased the number of neuronal CYLD positive cells in the ischemic cortical border region at 24 h reperfusion.

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CYLD decreases the amount of Cyclin. 3 / 3

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Indeed, CYLD is upregulated in injured carotid arteries of rats, reduces cyclin D1 levels, and is capable of suppressing vascular lesion formation.

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Also supporting this line of evidence is the finding that the tumor suppressor CYLD blocks cyclin D1 expression by inhibiting Bcl-3 signaling [XREF_BIBR].

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Modified CYLD decreases the amount of Cyclin. 2 / 2

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10,73 CYLD expression is repressed by the transcription factor SNAI1 in melanoma, resulting in increased cyclin D1 expression.

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CYLD overexpression also inhibited expression of cyclin D1 and activation of the E2F pathway through deubiquitination of the upstream molecule Bcl-3 and inhibition of its translocation into the nucleus.

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CYLD inhibits Cyclin.

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CYLD inhibits Cyclin. 2 / 2

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These findings indicate that Bcl-3 is required for the inhibitory effect of Cyld on TPA- and UV induced cyclin D1 activation and proliferation.To test whether the retention of Bcl-3 is dependent on th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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A potential area may be the downregulation of Cyclins by CYLD.

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Modified CYLD inhibits Cyclin. 1 / 1

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These results suggest that BCL-3-induced cyclin D1 and N-cadherin expression is blocked by the expression of CYLD.

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Mutated CYLD inhibits Cyclin. 1 / 1

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CYLD activates Cyclin.

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CYLD activates Cyclin. 2 / 2

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In agreement, down-regulation of CYLD in asSnail clones 1 and 2 resulted in up-regulation of Cyclin D1 and N-cadherin (XREF_FIG).

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Importantly, TPA or UV-B failed to activate the Mut-CD1 promoter in Cyld +/+ as well as Cyld -/- keratinocytes, indicating that Cyld modulates TPA- or UV-B-mediated cyclin D1 promoter activation in an[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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CYLD increases the amount of Cyclin.

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CYLD increases the amount of Cyclin. 1 / 1

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To examine whether Cyld increases cyclin D1 expression in keratinocytes through activation of NF-kappaB, we compared the activity of wild-type and NF-kappaB binding deficient cyclin D1 (Mut-CD1) promo[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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CYLD affects IKBKE

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CYLD activates IKBKE.

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CYLD activates IKBKE. 7 / 7

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Genetic deficiency in the DUB CYLD causes constitutive activation of TBK1 and IKKepsilon in DCs, rendering the cells hyperresponsive to VSV induced type I IFN expression XREF_BIBR, XREF_BIBR.

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CYLD deficiency causes constitutive activation of IKKepsilon and TBK1, which is associated with hyper-induction of IFNs in virus infected cells.

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CYLD deficiency causes constitutive activation of TBK1 and IKKepsilon in DCs, and the CYLD deficient DCs and MEFs are hyper-responsive to VSV in IFNbeta induction 80.

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CYLD deficiency causes constitutive activation of TBK1 and IKKε in DCs, and the CYLD-deficient DCs and MEFs are hyper-responsive to VSV in IFNβ induction xref .

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Although this phenotype may involve ubiquitin dependent activation of RIG-I, CYLD also directly targets TBK1 and IKKepsilon to inhibit their ubiquitination 79.

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CYLD inhibits IKBKE.

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CYLD inhibits IKBKE. 4 / 4

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CYLD also negatively regulates the IKK related kinases, IKKepsilon and TBK1, by the same mechanisms.

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The effect of CYLD was not specific to RIG-I, as CYLD also deubiquitinated and inhibited the signaling activities of TBK1 and IKKe.

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Our previous studies as well as others have demonstrated that A20, TAX1BP1, ABIN1 and CYLD inhibit TBK1 and IKKi by antagonizing their Lys63 linked polyubiquitation XREF_BIBR, XREF_BIBR, XREF_BIBR.

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The effect of CYLD was not specific to RIG-I, as CYLD also deubiquitinated and inhibited the signaling activities of TBK1 and IKKepsilon.

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CYLD affects (-)-noscapine

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CYLD activates (-)-noscapine.

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CYLD activates (-)-noscapine. 10 / 10

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Flow cytometry and immunofluorescence microscopy reveal that CYLD increases the ability of noscapine to induce mitotic arrest and apoptosis.

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CYLD enhances the effect of noscapine on microtubule polymerization.

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Based on the data presented in this work, we propose the following model for how CYLD promotes noscapine activity in leukemia cells.

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Thus, we examined whether CYLD modulates the ability of noscapine to cause mitotic arrest.

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In addition, flow cytometric analysis of DNA content showed that CYLD and its C/S mutant, but not its DeltaCG1 mutant, promoted the ability of noscapine to induce the accumulation of G2/M cells.

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To understand how CYLD modulates noscapine activity in leukemia cells, we transfected cells with GFP, GFP-CYLD, GFP-CYLD-DeltaCG1, in which the extreme N-terminal CAP-Gly domain of CYLD was deleted, or GFP-CYLD-C/S, in which cysteine 601 was mutated to serine to disrupt the deubiquitinase activity of CYLD.

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We found that CYLD, but not its DeltaCG1 mutant, significantly promoted the effect of noscapine on microtubule assembly in vitro.

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It is possible that CYLD may also exert on these pathways to stimulate noscapine activity.

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CYLD enhances noscapine activity to induce mitotic arrest and apoptosis in a microtubule dependent manner.

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Here we demonstrate that cylindromatosis (CYLD), a microtubule associated tumor suppressor protein, modulates the activity of noscapine both in cell lines and in primary cells of acute lymphoblastic leukemia (ALL).

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CYLD inhibits (-)-noscapine.

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CYLD inhibits (-)-noscapine. 1 / 1

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CYLD siRNAs inhibit the ability of noscapine to induce mitotic arrest and apoptosis in leukemia cell lines.

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PDE4B affects CYLD

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PDE4B decreases the amount of CYLD.

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PDE4B decreases the amount of CYLD. 6 / 6

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In the present study, we identified PDE4B as a key negative regulator for CYLD via selective activation of c-jun N-terminal kinase 2 (JNK2), but not JNK1, and inhibition of PDE4B significantly enhanced NTHi induced CYLD expression and suppressed inflammation.

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Taken together, it is evident that PDE4B negatively regulates CYLD expression and mediates NTHi induced inflammation via specific activation of JNK2 but not JNK1 pathway.

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In the present study, we showed that inhibition of PDE4B markedly enhanced upregulation of CYLD expression by the bacterial pathogen NTHi, thereby suggesting that PDE4B acts as a negative regulator for CYLD.

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Inhibition of PDE4B markedly increased the expression of CYLD and subsequently suppressed bacteria induced inflammation in well established models of both lung and middle ear inflammation.

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As shown in XREF_FIG, PDE4B knockdown selectively inhibited activation of JNK2 but not JNK1, thereby confirming that PDE4B negatively regulates NTHi induced CYLD expression and mediates inflammation via specific activation of JNK2 but not JNK1.

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These results suggest that PDE4B negatively regulates CYLD expression and mediates inflammation via the JNK pathway.

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PDE4B inhibits CYLD.

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PDE4B inhibits CYLD. 4 / 4

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For example, inhibiting PDE4B in an HMEEC cell line caused an upregulation of CYLD and a concomitant reduction in inflammation [XREF_BIBR].

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Moreover, PDE4B negatively regulates CYLD via selective activation of JNK2 but not JNK1.

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PDE4B downregulates CYLD via activation of JNK2 pathway.

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Moreover, PDE4B negatively regulates CYLD via specific activation of JNK2 but not JNK1.

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PDE4B activates CYLD.

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PDE4B activates CYLD. 1 / 1

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PDE4B mediates inflammation by downregulating CYLD.

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CYLD affects IKK_complex

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CYLD inhibits IKK_complex. 10 / 10

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Cyld -deficient mice have been generated by different groups, and these mice display a myriad of phenotypes that overall support the conclusion that CYLD inhibits IKK and NF-kappaB and contributes, at[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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These observations suggest that suppression of CYLD enhances the activity of the IKK kinase and the nuclear localization of NF-kappaB transcription factors.

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Notch is capable of enhancing NF-kappaB activity by a Hes1 dependent mechanism (Hes1 mediated suppression of Cyld, a deubiquitinase that negatively regulates the IKK complex) 53 and Hes1 independent mechanisms (NICD induced expression of NF-kappaB, NICD enhanced IKKalpha activity, or NICD mediated NF-kappaB nuclear retention) XREF_BIBR - XREF_BIBR.

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The effect of CYLD was not specific to RIG-I, as CYLD also deubiquitinated and inhibited the signaling activities of TBK1 and IKKɛ.

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CYLD inhibits IKK by cleaving K63-linked polyubiquitin chains on TRAF2, TRAF6 and NEMO xref , xref Interestingly, in patients with the cylindromas (a type of tumor), a mutation in the DUB domains of CYLD has been reported, suggesting its role of tumorgenesis xref .

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We further demonstrate that CYLD also negatively regulates IkappaB kinase, although this function of CYLD is seen in a receptor dependent manner.

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CYLD inhibits Tax stimulated activation of IKK but not that of Tak1.

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These include the deubiquitination enzymes CYLD and A20 that inhibit IKK, and the ubiquitin binding proteins NEMO and TAB2 which are the regulatory subunits of IKK and TAK1 kinase complexes, respectively.

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Conversely, loss of the K63 specific deubiquitinase CYLD causes spontaneous activation of IKK and JNK as well as their upstream kinase Tak1.

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CYLD affects HDAC6

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CYLD inhibits HDAC6. 10 / 10

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Moreover, CYLD is also able to inhibit HDAC6, a member of the HDAC family whose major substrate is α-tubulin, has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation xref .

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CYLD mediated HDAC6 inhibition was observed to enhance its association with the MTs, reduce the rate of cytokinesis, and delay cell cycle (XREF_FIG).

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CYLD also inhibits HDAC6, leading to increased acetylated tubulin and less cellular motility, as we saw before [XREF_BIBR].

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Moreover, CYLD is also able to inhibit HDAC6, a member of the HDAC family whose major substrate is alpha-tubulin, has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation XREF_BIBR.

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CYLD interacts with p62 directly and CYLD can directly inactivate HDAC6, thereby controlling autophagy [ xref ].

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In addition, CYLD inactivates HDAC6, which modulates cilia length [XREF_BIBR].

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We further found by immunofluorescence microscopy a colocalization of CYLD and HDAC6 at the centrosome and basal body and, interestingly, loss of Cyld promoted the localization of HDAC6 at the centrosome and basal body.

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In addition, CYLD inactivates HDAC6, which modulates cilia length [ xref ].

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CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin.

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Taken together, these findings suggest that CYLD, TSA, and tubacin act within the same pathway to inhibit HDAC6, which results in elevated levels of acetylated alpha-tubulin.

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SPATA2 affects CYLD

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SPATA2 activates CYLD.

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SPATA2 activates CYLD. 9 / 9

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SPATA2 promotes CYLD activity and regulates TNF induced NF-kappaB signaling and cell death.

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Finally, the finding that SPATA2 activates CYLD adds SPATA2 to the growing list of allosteric DUB activators.

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The location of the SPATA2 binding site at the back of the palm domain suggests that SPATA2 activates CYLD in a distinct manner.

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To directly address if SPATA2 mediates the ability of CYLD to regulate baseline NF-kappaB activity, we ectopically expressed CYLD in WT, CYLD KO, and SPATA2 KO cells.

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The location of the SPATA2 binding site at the back of the palm domain suggests that SPATA2 activates CYLD in a distinct manner.

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SPATA2 Activates CYLD.

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Finally, the finding that SPATA2 activates CYLD adds SPATA2 to the growing list of allosteric DUB activators.

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SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling.

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SPATA2 Activates CYLD.

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SPATA2 inhibits CYLD.

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SPATA2 inhibits CYLD. 1 / 1

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The fact that KO of SPATA2 already prevents association of CYLD with the TNFR1 (XREF_FIG D) indicates that SPATA2L can not simply substitute for SPATA2, at least in the cellular systems tested.

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Phorbol 13-acetate 12-myristate affects CYLD

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Phorbol 13-acetate 12-myristate activates CYLD.

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Phorbol 13-acetate 12-myristate activates CYLD. 8 / 8

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This is supported by the finding that depletion of HDAC6 was not sufficient to induce the interaction of CYLD with Bcl-3, but TPA mediated activation of CYLD is additionally required.

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Interaction of CYLD with tubulin and MT. We have earlier shown that UV or TPA treatment of primary mouse keratinocytes triggers perinuclear accumulation of CYLD, which correlates with its ability to interact with its downstream targets.

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These data suggest that TPA increases tumor promotion in Cyld -/- mice by enhancing tumor cell proliferation.

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As expected, TPA induced interaction of CYLD with Bcl-3, while this interaction (XREF_FIG), as well as perinuclear localization of CYLD (XREF_SUPPLEMENTARY), was prevented in the presence of nocodazole.

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TPA stimulated Cyld +/+ keratinocytes and EGFP-CYLD-expressing melanoma cells showed reduced levels of BrdU positive nuclei as an indication of delayed S-phase progression in the presence of activated CYLD (XREF_FIG).

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Importantly, nuclear accumulation of Bcl-3 was also significantly increased in DMBA and TPA induced Cyld -/- tumors when compared with tumors from control littermates.

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GATD3B inhibits CYLD. 5 / 5

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The mechanism of Notch induced NF-kappaB activation in T-ALL involves Hes1, which transcriptionally represses CYLD (cylindromatosis), a deubiquitinase which down-regulates NF-kappaB signaling by removing the activator K63 ubiquitin chains from different elements of the NF-kappaB signalosome [XREF_BIBR].

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Hes1 downregulated CYLD, a negative regulator of NF-kappaB signalling, and then activated the IKK/IkappaBalpha/NF-kappaB signalling pathway.

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It has been reported that NF-kappaB is activated via NICD and Hes1 mediated repression of the deubiquitinase CYLD and has a crucial role in the survival and drug resistance of T-ALL cells.

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The experiments performed by Espinosa and collaborators [XREF_BIBR] in T-ALL and HEK293T cells support the notion that HES1 induced CYLD repression results in increased IKK kinase activity, IkappaBalpha degradation, RelA nuclear translocation, and NF-kappaB transcriptional activity.

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Similarly, CYLD is downregulated by Notch and Hes1 in T-cell acute lymphoblastic lymphoma (T-ALL), thus leading to constitutive NF-kappaB activation.

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While ectopic expression of a dominant negative Hes1 (dN-Hes1) upregulated Cyld expression, luminal sphere forming activity was not affected (XREF_FIG), suggesting that Hes1 mediated Cyld suppression does not play a role in NF-kappaB-mediated survival of luminal prostate sphere forming cells.

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CYLD affects transcription, DNA-templated

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CYLD inhibits transcription, DNA-templated.

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CYLD inhibits transcription, DNA-templated. 6 / 6

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CYLD has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-kappaB.

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The tumor suppressor gene CYLD, which was recently identified as the cylindromatosis gene, has a deubiquitinating enzyme (DUB) activity and inhibits activation of the transcription factor NF-kappaB, which has key roles in inflammation, immune responses, carcinogenesis, and protection against apoptosis [XREF_BIBR].

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CYLD, a tumor suppressor gene, has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-kappaB.

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Consequently, CYLD inhibits the activation of the transcription factor NF-kappaB, which plays an important role for immune responses.

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These observations suggest that suppression of CYLD enhances the activity of the IKK kinase and the nuclear localization of NF-kappaB transcription factors.

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In the search for the tumor suppressor function of CYLD, several laboratories reported that CYLD can inhibit the activation of the classical NF-kappaB p65 and p50 transcription factor (Trompouki et al[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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CYLD activates transcription, DNA-templated.

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CYLD activates transcription, DNA-templated. 3 / 3

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Our study supported the involvement of six candidate genes in susceptibility to psoriasis : SCL12A8, which belongs to the solute carrier gene family; FLG and TGM5, which are involved in epidermal differentiation; CARD15 and CYLD, which modulate the transcription factor NF-kB; and IL1RN, which encodes an IL receptor antagonist.

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These researchers found that the familial cylindromatosis tumour suppressor gene (CYLD), previously of unknown function, could enhance the activation of the transcription factor NF-kappaB, leading to increased resistance to apoptosis.

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CYLD (the familial cylindromatosis tumor suppressor gene) enhances the activation of the transcription factor NFkapa-B [XREF_BIBR], RBBP6, (which binds to the retinoblastoma gene product pRB) [XREF_BIBR], and PNUTL2 (which is an apoptosis related protein in the TGF-beta signaling pathway) [XREF_BIBR].

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CYLD affects AP1

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CYLD inhibits AP1.

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CYLD inhibits AP1. 5 / 5

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CYLD loss-of-function promotes human SCC in an AP1 dependent manner.

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We found that CYLD m increased AP1 driven expression both in the presence and absence of EGF; whereas CYLD WT reduced AP1 activity in both conditions (XREF_FIG).

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In contrast, expression of the wild type CYLD inhibited SCC tumorigenesis and AP1 function.

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Taken together, these findings indicated that CYLD negatively regulates the activation of TAK1, p38, and AP-1.

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We therefore examined whether the loss of CYLD also promoted the activation of AP-1.

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CYLD activates AP1.

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CYLD activates AP1. 4 / 4

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In addition, CYLD WT markedly reduced while CYLD m significantly potentiated AP1 activity driven by exogenous c-Fos expression; conversely, gene silencing of c-Jun or c-Fos abolished AP1-induction by CYLD m (XREF_FIG).

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Thus, the exact mechanism of MALT1- and CYLD-dependent AP-1 activation and the role of JNK in this pathway remain to be further explored.

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CYLD Inhibits Tumorigenesis and Metastasis by Blocking JNK and AP1 Signaling at Multiple Levels.

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We found that CYLD m increased AP1 driven expression both in the presence and absence of EGF; whereas CYLD WT reduced AP1 activity in both conditions (XREF_FIG).

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Notch affects CYLD

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Notch decreases the amount of CYLD.

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Notch decreases the amount of CYLD. 5 / 5

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The results showed that blockade of Notch signal up-regulated expression of CYLD in BMDMs treated with CM from I/R injured hepatocytes (XREF_FIG).

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Previous reports have demonstrated that Notch signal represses the expression of CYLD that negatively regulates NF-kappaB activation in macrophages XREF_BIBR.

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On the other hand, activation of Notch signaling in macrophages led to increased inflammatory cytokine production and NF-kappaB activation and decreased CYLD expression in vitro.

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In T cell acute lymphoblastic leukemia (T-ALL), CYLD expression is repressed by the Notch and Hes1 pathway to promote persistent IKK activation and cell survival [XREF_BIBR].

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Notch inhibits CYLD.

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Notch inhibits CYLD. 3 / 3

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Similarly, CYLD is downregulated by Notch and Hes1 in T-cell acute lymphoblastic lymphoma (T-ALL), thus leading to constitutive NF-kappaB activation.

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Notch activation in CYLD siRNA transfected cells was normalised to cells transfected with non silencing siRNA.

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Therefore, we reasoned that fibulin-3 stimulation of Notch could downregulate CYLD and indirectly activate NF-kappaB.

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Notch activates CYLD.

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Notch activates CYLD. 1 / 1

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Surprisingly, blockade of Notch signaling with the gamma-secretase inhibitor DAPT 17 did not prevent the downregulation of CYLD (XREF_FIG) and the activation of NF-kappaB p65 (XREF_FIG) by fibulin-3.

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IKBKE affects CYLD

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IKBKE inhibits CYLD.

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IKBKE inhibits CYLD. 5 / 5

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A similar mechanism is thought to occur in breast carcinogenesis where IKKε phosphorylates and inactivates CYLD ( xref ).

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IKKepsilon inhibits CYLD activity through phosphorylation, which results in the blockage of the deubiquination of TRAF2 and NF-kB essential modulator (NEMO), positive regulators of the classical NF-kB pathway.

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In addition, IKKepsilon has been reported to decrease the activity of CYLD, a deubiquitinating enzyme that negatively regulates IRF3/7 activation, thereby indirectly increasing IRF mediated signaling [XREF_BIBR, XREF_BIBR].

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IKKɛ also phosphorylates and inactivates the tumor suppressor CYLD, preventing CYLD from deubiquitinating specific substrates in the NF-κB signaling pathway.

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IKKe also phosphorylates and inactivates the tumor suppressor CYLD, preventing CYLD from deubiquitinating specific substrates in the NF-kB signaling pathway.

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IKBKE activates CYLD.

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IKKepsilon also phosphorylates and inactivates the tumor suppressor CYLD , preventing CYLD from deubiquitinating specific substrates in the NF-kappaB signaling pathway .

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IKKe also phosphorylates and inactivates the tumor suppressor CYLD , preventing CYLD from deubiquitinating specific substrates in the NF-kB signaling pathway .

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Moreover, we recognize that IKKepsilon may also modulate other substrates in addition to CYLD during cell transformation.

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IKBKE increases the amount of CYLD.

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IKBKE increases the amount of CYLD. 1 / 1

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TBK1 and IKKi dual inhibitors suppress the expressions of p-CYLD and p-AKT, and angiogenesis.

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CYLD affects signal transduction

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CYLD inhibits signal transduction.

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CYLD inhibits signal transduction. 6 / 6

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In this study, we used transgenic mouse and human SCC models to investigate how CYLD loss-of-function leads to abnormal signal transduction and promotes tumorigenesis.

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CYLD is a deubiquitination enzyme targeting lysine 63 linked ubiquitin chains and was shown to negatively regulate signal transduction factors and pathways including transforming growth factor-beta and NF-kappaB signaling pathways [XREF_BIBR - XREF_BIBR].

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As both CYLD and OTULIN negatively regulate the NF-kappaB signalling cascade, the impact of these deubiquitinases in different LUBAC dependent signalling cascades may be context dependent.

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It has been proposed that CYLD inhibits proinflammatory signal transduction [23,35] .

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Ectopic expression of CYLD inhibits the IRF3 signalling pathway and IFN production triggered by RIG-I; conversely, CYLD knockdown enhances the response.

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These findings suggest that CYLD can both positively and negatively regulate signal transduction and homeostasis of B cells in vivo, depending on the expression of CYLD splice variants.

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CYLD bound to IKBKG inhibits signal transduction. 1 / 1

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CYLD interacts with NEMO, TNF receptor associated factor (TRAF)-2, and TRAF interacting protein and negatively regulates the canonical NF- kappa B signal transduction pathway (Brummelkamp et al., 2003[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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CYLD activates signal transduction.

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CYLD activates signal transduction. 2 / 2

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Treatment of MEFs with either 12-O-tetradecanoylphorbol-13 acetate (TPA) (XREF_FIG) or TNF-alpha (XREF_FIG) which was shown earlier to regulate CYLD mediated signal transduction XREF_BIBR, XREF_BIBR, were unable to increase the proliferation rate of CYLD-/- MEFs compared to CYLD +/+ over a period of 24-96 hours (XREF_FIG).

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A proposed model explaining how p62 mutations lead to the Paget's disease of bone is the following: mutations of the UBA domain cause an impairment in the interaction between p62 and ubiquitinated TRAF6 and/or CYLD, an enzyme deubiquitinating TRAF6, which in turn enhances the activation of the NF-κB signaling pathway and the resulting increased osteoclastogenesis (Figure 3(b)) [160].

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CYLD affects TP53

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CYLD activates TP53.

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CYLD activates TP53. 5 / 5

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In addition, overexpression of HA-CYLD diminished the ubiquitination and increased the stabilization of endogenous p53 in CpT treated HCT116 cells (XREF_FIG).

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Moreover, CYLD was predicted to regulate p53 in an unbiased bioinformatics approach aiming to build a functional human protein interaction network by combining protein interaction, gene expression and gene ontology annotations with genome-wide cancer data sets XREF_BIBR, further supporting that regulation of p53 signalling by CYLD is functionally relevant for human cancer.

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Recently, CYLD was shown to promote DNA damage induced p53 stabilization and activation in epithelial cells and inhibit chemical carcinogen induced intestinal and skin tumorigenesis [XREF_BIBR].

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Additionally, CYLD upregulated p53 by about 2-fold, which was diminished by c-Jun and MKK7 (XREF_FIG).

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We found that HA-CYLD expressed in HEK-293T cells co-immunoprecipitated with endogenous p53 or overexpressed GFP-p53 in reciprocal IPs and that this interaction was enhanced after DNA damage (XREF_FIG).

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CYLD inhibits TP53.

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CYLD inhibits TP53. 3 / 3

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Therefore, lack of CYLD catalytic activity inhibited the p53 dependent death of IECs in response to DNA damage in vivo and in vitro.

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We did not directly address the specific role of the proteasome in mediating CYLD induced degradation of p53, as any experiment involving proteasome inhibition would result in p53 stabilization and thus would be inconclusive in proving the specific role of CYLD.

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The role of CYLD in regulating p53 is evolutionarily conserved as shown by our findings that CYLD deficiency impairs p53 dependent DNA damage induced germ cell apoptosis in C. elegans.

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CYLD increases the amount of TP53.

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CYLD increases the amount of TP53. 1 / 1

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Moreover, CYLD induced an array of other molecular changes associated with modulation of the ' malignant ' phenotype, including a decreased expression of cyclin D1, N-cadherin and nuclear Bcl3, and an increased expression of p53 and E-cadherin.

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CYLD affects TGFB

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CYLD inhibits TGFB.

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CYLD inhibits TGFB. 7 / 7

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Finally, the deubiquitylase CYLD inhibits TGF-beta signaling by decreasing the stability of Smad3.

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CYLD also negatively regulates signaling and TGFbeta responsiveness, suppressing extrathymic Treg induction and the pTreg pool.

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The deubiquitylating enzyme CYLD additionally inhibits TGF-beta signaling by forming a complex with Smad7 and facilitates its deubiquitylation at two sites in its MH2 domain.

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CYLD negatively regulates TGFbeta responsiveness, adversely affecting extrathymic Treg induction and the pTreg pool.

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It is interesting that CYLD knockdown promoted transforming growth factor-beta (TGF-beta) signalling by inducing stabilization of TGF-beta receptor I (ALK5) in a cell autonomous fashion.

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CYLD activates DUSP1. 5 / 5

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Having shown that CYLD negatively regulates NTHi induced IL-8 expression via the inhibition of ERK and positively regulates MKP-1, we next investigated whether CYLD acts as a negative regulator for ERK dependent IL-8 induction via MKP-1.

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CYLD also enhanced NTHi induced upregulation of MAP kinase phosphatase-1, which led to reduced ERK activation and subsequent suppression of IL-8.

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Therefore, investigating the molecular mechanisms of how CYLD upregulates MKP-1 may bring new insights into the tight regulation of inflammatory responses.

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Taken together, our data suggest that CYLD mediates NTHi induced upregulation of MKP-1.

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Because CYLD has been identified as a DUB, we investigated whether DUB activity is required for the CYLD mediated upregulation of MKP-1 induced by NTHi.

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CYLD increases the amount of DUSP1.

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CYLD increases the amount of DUSP1. 2 / 2

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Thus, our data demonstrate that CYLD upregulates MKP-1 expression in a DUB activity dependent manner.

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CYLD inhibits innate immune response. 8 / 8

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Interestingly, CYLD is reported to negatively regulate the innate immune response to infection by Listeria monocytogenes, an intracellular bacterial pathogen recognized by NOD1 and NOD2.

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The higher sensitivity of Cyld -/- mice to DSS induced inflammation indicates a role for CYLD in the negative regulation of the mucosal innate immune response to microorganisms.

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Three human DUBs, CYLD, A20 and DUBA, have been shown to negatively regulate the innate immune response by removing K63-based chains [55, 56] , and USP15 inhibits the NFkB pathway by removing K48-Ub from IkBa, preventing its degradation [57] .

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CYLD inhibits activation of nuclear factor-kappaB (NF-kappaB) and innate immune response.

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Three human DUBs, CYLD, A20 and DUBA, have been shown to negatively regulate the innate immune response by removing K63-based chains [55], [56], and USP15 inhibits the NFκB pathway by removing K48-Ub from IκBα, preventing its degradation [57].

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Cellular proteins DUBA and CYLD also negatively regulate the innate immune response.

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Three human DUBs, CYLD, A20 and DUBA, have been shown to negatively regulate the innate immune response by removing K63 based chains XREF_BIBR, XREF_BIBR, and USP15 inhibits the NFkappaB pathway by removing K48-Ub from IkappaBalpha, preventing its degradation XREF_BIBR.

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CYLD affects TNFRSF11A

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CYLD inhibits TNFRSF11A. 8 / 8

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Deubiquitinating enzyme cylindromatosis (CYLD) has been shown to negatively regulate RANK ligand-RANK signaling essential for OCL differentiation.

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Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice.

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Thus, CYLD inhibits RANK mediated signaling function by deubiquitinating TRAF6 or its downstream targets involved in NF-kappaB activation.

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CYLD inhibits RANK mediated signaling in osteoclasts in a negative feedback loop by deubiquitinating TRAF6 (XREF_FIG).

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The deubiquitinating enzyme, CYLD has been shown to interact with p62 UBA domain to inhibit TRAF6 ubiquitination and thereby negatively regulates RANK signaling and osteoclastogenesis.

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In addition, CYLD negatively regulates RANK signaling, which is known to be a key factor in bone resorption in cholesteatoma [XREF_BIBR].

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Interestingly, CYLD has been shown to negatively regulate RANK signalling and osteoclastogenesis in mice [XREF_BIBR].

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CYLD affects STAT3

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CYLD inhibits STAT3.

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CYLD inhibits STAT3. 7 / 7

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CYLD reduced activation of p65, JAK2, STAT3, and p38 MAPK as well as fibrin production in livers of Listeria infected WT mice.

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In WT mice, IL-6 neutralization only slightly reduced pSTAT3 without affecting fibrin (XREF_FIG) indicating that IL-6 induced pSTAT3 is strongly regulated by CYLD, which limits STAT3 activity and STAT3 dependent fibrin production.

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CYLD knockdown resulted in an increase of pSTAT3 (XREF_FIG) as well as fibrin (XREF_FIG) in Lm infected WT mice.

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In extension, we newly identified that IL-6 does not only induce STAT3 phosphorylation in hepatocytes XREF_BIBR, but that CYLD strongly reduced IL-6-dependent accumulation of activated STAT3 in hepatic nuclei.

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The observation that siRNA mediated inhibition of CYLD in WT mice increased hepatic p-STAT3 and fibrin levels, diminished hemorrhage and significantly increased survival indicates that inhibition of CYLD might be a therapeutic option in severe listeriosis and potentially other infectious diseases including acute lung injury induced by S. pneumoniae XREF_BIBR.

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In extension to current knowledge, we uncover that the CYLD dependent suppression of STAT3 activity in hepatocytes resulted in a decreased fibrin production, which identifies CYLD as an important regulator of IL-6-induced STAT3 dependent fibrin production.

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In addition, CYLD diminished IL-6-induced STAT3 activity by reducing nuclear accumulation of phosphorylated STAT3.

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CYLD activates STAT3.

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CYLD activates STAT3. 1 / 1

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CYLD impairs production of fibrin in Listeria infection in mice by inhibiting NF-kB-mediated activation of IL-6 production and IL-6 's activation of the STAT3 pathway that leads to fibrosis [XREF_BIBR].

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CYLD affects IL6

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CYLD inhibits IL6.

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CYLD inhibits IL6. 6 / 6

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CYLD overexpression clearly inhibited hypoxia induced synthesis and secretion of IL-6.

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In fact, CYLD overexpression significantly inhibited hypoxia triggered induction of IL-6 and IL-8.

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CYLD Enhances Severe Listeriosis by Impairing IL-6 and STAT3-Dependent Fibrin Production.

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Previously, we have shown that CYLD inhibits IL-6 production by macrophages, which in turn induces STAT3 dependent protective fibrin production by hepatocytes in listeriosis.

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CYLD reduced IL-6, ROS production and killing of Lm in Listeria infected macrophages by impairing NF-kappaB activation.

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In fact, CYLD overexpression completely blocked hypoxia mediated induction of those inflammatory mediators and suppressed basal expression of some cytokines (IL-6, IL-8, IL1beta, IL-1F5, IL-1F8, and CXCL2).

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CYLD activates IL6.

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CYLD activates IL6. 2 / 2

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CYLD affects localization

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CYLD inhibits localization.

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CYLD inhibits localization. 6 / 6

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These observations suggest that suppression of CYLD enhances the activity of the IKK kinase and the nuclear localization of NF-kappaB transcription factors.

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While the molecular mechanisms by which these proteins regulate the ciliary role of HDAC6 are elusive, our data demonstrate that HDAC6 is enriched at the centrosome and basal body and that this localization is enhanced by the loss of Cyld.

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The inhibitory action of Bcl-3 nuclear translocation is executed by the tumour suppressor protein cylindromatosis (CYLD), which can bind directly to Bcl-3 and prevent its nuclear localization [XREF_BIBR].

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Loss of CYLD in HMCLs was found to enhance beta-catenin stabilization and localization to the nucleus, increase beta-catenin-LEF and TCF reporter activity, and enhance MM cell growth and survival.

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Interestingly, the ubiquitin ligase CYLD, which negatively regulates bcl3 nuclear localization, was increased 2.7-fold in the RNA-Seq analysis (XREF_SUPPLEMENTARY).

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CYLD bound to CEP350 inhibits localization. 1 / 1

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CYLD activates localization.

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CYLD activates localization. 1 / 1

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Moreover, this M719V variant of CYLD impairs autophagosome maturation and increases the cytosolic localization of TDP-43.

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CYLD affects RHOA

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CYLD activates RHOA.

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CYLD activates RHOA. 5 / 5

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These findings prompted us to investigate whether CYLD modulates other Rho family members.

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We thus studied whether CYLD promoted RhoA activity by interacting with LARG.

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In agreement with the CYLD shRNA result, overexpression of GFP-CYLD promoted RhoA activity (XREF_FIG).

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Notably, we also show that MYB drives the proliferation of CYLD defective cylindroma cells.

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Overexpression of MYB is known to drive proliferation of CYLD defective cylindroma cells, and molecular heterogeneity in the pathogenesis of sporadic and inherited cutaneous cylindromas appears to converge on MYB activation [XREF_BIBR].

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CYLD defective cylindroma cells were treated with MYB siRNAs for 72h, after which total cellular protein was prepared by lysing cells in RIPA lysis buffer (Millipore) supplemented with complete Mini Protease Inhibitors (Roche).

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This resulted in a significant inhibition of MYB target genes and proliferation of cylindroma cells from three independent tumours, suggesting that MYB activation drives the growth of CYLD defective cylindromas and potentially also the growth of MYB-NFIB-positive sporadic cylindromas.

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MYB promotes the proliferation of CYLD defective cylindroma cells.

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CYLD defective cylindroma cells were treated with MYB siRNAs for 48h before total RNA was extracted using an RNeasy Micro-kit (Qiagen).

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CYLD defective cylindroma cells were treated with MYB siRNAs for 6 consecutive days, after which cell proliferation was assayed using Alamar Blue Reagent (Thermo Fisher Scientific) and a VICTOR-3 multilabel reader (Perkin-Elmer), according to instructions supplied by the manufacturers.

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OPTN affects CYLD

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OPTN activates CYLD.

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OPTN activates CYLD. 5 / 5

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The main feature of this model is that optineurin mediates binding of CYLD to ubiquitinated RIP.

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We further showed that Optn targets the deubiquitinase CYLD to TBK1 in order to downregulate the antiviral innate immune pathway.

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We therefore concluded that Optn targets the deubiquitinase activity of CYLD to TBK1 to prevent its activity and to dampen the antiviral response.

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Furthermore, optineurin inhibits the antiviral innate immune response by targetting CYLD to TBK1 to suppress its kinase activity, subsequently inhibiting interferon production.

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The results presented in this manuscript suggest that optineurin mediates interaction of deubiquitinase CYLD with polyubiquitinated RIP and this interaction is essential for deubiquitination of RIP by CYLD.

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OPTN inhibits CYLD.

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OPTN inhibits CYLD. 2 / 2

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Of note, optineurin, a gene in one of the other Paget 's susceptibility loci can also attenuate TNF-alpha signaling by recruiting CYLD to RIP1.

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In conclusion, our observations strongly suggest that optineurin mediates targeting of CYLD to its substrate (i.e ubiquitinated RIP) which facilitates its deubiquitination.

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MIR21 affects CYLD

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MIR21 activates CYLD.

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MIR21 activates CYLD. 4 / 4

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MiR-21 and miR-181b act as an epigenetic switch to inhibit PTEN and CYLD tumor suppressors, leading to increased NF-kB activity required to maintain the transformed state XREF_BIBR.

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STAT-3 directly activates miR-21 and miR-181b-1, which inhibit PTEN and CYLD tumor suppressors, leading to increased NF-κB activity required to maintain the transformed state.

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STAT-3 directly activates miR-21 and miR-181b-1, which inhibit PTEN and CYLD tumor suppressors, leading to increased NF-jB activity required to maintain the transformed state.

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STAT-3 directly activates miR-21 and miR-181b-1, which inhibit PTEN and CYLD tumor suppressors, leading to increased NF-kappaB activity required to maintain the transformed state.

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MIR21 inhibits CYLD.

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MIR21 inhibits CYLD. 3 / 3

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has shown that miR-21, together with miR-181b-1, inhibit PTEN and cylindromatosis (CYLD) tumor suppressor functions, respectively, leading to increased NF-kB activity thus underlying the epigenetic switch that links inflammation to cancer.

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IL-6 also activates STAT3 causing direct activation of miR-21 and miR-18b-1, which respectively inhibit PTEN and CYLD (tumor suppressor genes).

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This suggests that these miRNAs are part of the regulatory circuit, and indeed they found that their expression is regulated by IL-6 and that both miR-21 and miR-181b-1 can activate NF-kappaB by targeting and inhibiting the tumour suppressors PTEN and CYLD [XREF_BIBR].

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IKBKB affects CYLD

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IKBKB inhibits CYLD.

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Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.

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The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.

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IKBKB activates CYLD.

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CYLD affects Fibrin

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CYLD inhibits Fibrin.

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CYLD inhibits Fibrin. 6 / 6

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Before, we have shown that CYLD inhibits protective fibrin production by hepatocytes in listeriosis.

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In addition, in vivo Cyld siRNA treatment increased STAT3 phosphorylation, fibrin production, pathogen control and survival of Lm infected WT mice illustrating that therapeutic inhibition of CYLD augments the protective NF-kappaB/IL-6/STAT3 pathway and fibrin production.

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23825949

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CYLD reduced activation of p65, JAK2, STAT3, and p38 MAPK as well as fibrin production in livers of Listeria infected WT mice.

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23825949

CYLD activates Fibrin.

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CYLD activates Fibrin. 1 / 1

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23825949

CHUK affects CYLD

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CHUK inhibits CYLD.

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CHUK inhibits CYLD. 5 / 5

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Thus, serine 418 is phosphorylated in vivo. Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.

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CHUK activates CYLD.

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CYLD affects Wnt

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CYLD inhibits Wnt.

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CYLD inhibits Wnt. 3 / 3

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In addition, CYLD was proposed to inhibit Wnt signalling by deubiquitinating dishevelled XREF_BIBR.

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In human cylindroma, CYLD negatively regulates Wnt and beta-catenin signaling via deubiquitination of Dishevelled, which is a key component in Wnt mediated beta-catenin nuclear translocation.

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Increased CYLD expression may likewise diminish Wnt pathway activation and beta-catenin accumulation (XREF_FIG) via K63 linked deubiquitination of Dvl.

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CYLD activates Wnt.

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CYLD activates Wnt. 3 / 3

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Therefore, the activity of this DUB should stimulate rather than attenuate the signalling activity of Dvl, which means that the observed downregulation of Wnt signalling by CYLD XREF_BIBR can not be explained by its effect on Dvl polymerization.

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Loss of the tumor suppressor CYLD enhances Wnt and beta-catenin signaling through K63 linked ubiquitination of Dvl.

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The DIX domain is ubiquitinated in vivo at multiple lysines, which can be antagonized by various deubiquitinases (DUBs) including the CYLD tumour suppressor that attenuates Wnt signalling.

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CYLD increases the amount of Wnt.

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CYLD increases the amount of Wnt. 1 / 1

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Knockdown of CYLD in cultured cells strongly enhances Wnt induced beta-catenin stabilization and target gene transcription.

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Valproic acid affects CYLD

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Valproic acid increases the amount of CYLD. 6 / 6

6 |

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No evidence text available

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No evidence text available

19101580

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No evidence text available

26272509

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ctd

No evidence text available

21318169

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ctd

No evidence text available

22083351

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No evidence text available

23179753

MAP3K7 affects CYLD

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MAP3K7 activates CYLD. 6 / 6

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These data collectively suggest that sustained Tak1 activation in Itch -/- and Cyld -/- BMDMs results in chronic production of proinflammatory cytokines.

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Tak1 activation in Itch -/- and Cyld -/- BMDMs.

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To determine whether Tak1 is a functional target of CYLD, we analyzed the effect of CYLD on Tak1 ubiquitination.

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27 Of note, deregulated Tak1 ubiquitination also contributes to the hyperactivation of NF-kappaB and JNK in CYLD deficient T cells, 26 suggesting that Tak1 is a common target of CYLD in the innate and adaptive immune responses.

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Furthermore, consistent with the constitutive Tak1 activation in Cyld -/- T cells, transfected CYLD potently suppressed the catalytic activity of Tak1 (XREF_FIG).

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In mature T cells, CYLD targets TAK1 for inactivation to downregulate IKK and NF-kappaB activation [XREF_BIBR].

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CYLD affects IKBKB

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CYLD inhibits IKBKB. 6 / 6

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We next used an alternative approach to confirm that the loss of CYLD in T cells causes the constitutive activation of IKKbeta.

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However, because Cyld deficiency did not cause the activation of ERK, the target of CYLD might be an intermediate signaling factor specifically mediating the activation of JNK and IKKbeta.

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YM155 activated CYLD activity which led to suppressed IKKbeta activity and stabilization of inhibitory IkappaBalpha.

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Augmented CYLD activity suppressed IKKbeta which stabilized IkappaBalpha and retained NF-kappaB dimers in their inactive states in the cytosol.

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Surprisingly, the loss of CYLD did not result in the basal activation of IKKbeta or Tak1 in macrophages.

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These results establish a pivotal role for CYLD in controlling Tak1 function and explain how CYLD negatively regulates IKKbeta and JNK.

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CAMK2_complex affects CYLD

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CAMK2_complex activates CYLD. 6 / 6

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Since CYLD is a major protein in isolated PSDs XREF_BIBR and is phosphorylated by CaMKII, it is presumed that the observed changes in deubiquitination are a result of CaMKII mediated activation of CYLD.

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It was previously shown that, under excitatory conditions, CaMKII activates CYLD in a Ca 2+ -dependent manner.

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These results with purified proteins show that CaMKII activates CYLD via phosphorylation.

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These results with purified proteins show that CaMKII activates CYLD via phosphorylation.

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It was previously shown that, under excitatory conditions, CaMKII activates CYLD in a Ca 2+ -dependent manner.

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Activation of CaMKII by the addition of ATP promotes activation of CYLD, as indicated by the increase in the rate of degradation of polyubiquitins (XREF_FIG).

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Glucose affects CYLD

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Glucose decreases the amount of CYLD.

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Glucose decreases the amount of CYLD. 5 / 5

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Our data showed that high glucose significantly inhibited the protein and mRNA expression of CYLD in a dose- and time dependent manner (both p < 0.05).

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High Glucose Inhibits the Expression of CYLD in GMCs.

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In conclusion, the present study found that high glucose significantly inhibited the expression of CYLD and activated NF-kappaB inflammatory signaling in a dose- and time dependent manner.

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These data suggest that high glucose inhibited CYLD expression in GMCs (SV40 MES 13 and HBZY-1) in a time- and dose dependent manner.

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Glucose inhibits CYLD.

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Glucose inhibits CYLD. 1 / 1

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Compared with the NC group, the relative CYLD mRNA and protein expressions were inhibited by different concentrations of high glucose at 24h, particularly in the 30mmol/L glucose group (p < 0.05; XREF_FIG).

29259980

CYLD affects cell migration

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CYLD activates cell migration.

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CYLD activates cell migration. 4 / 4

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In contrast to the proliferation related activity, CYLD knockdown significantly decreased the cell migration of all the melanoma cell lines (n = 7, p < 0.05), and we demonstrated that the mechanism regulating melanoma cell migration was activation of RAC1 through the action of CYLD.

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CYLD has also been shown to stimulate cell migration and thereby contribute to normal physiological processes.

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Catalytic domain mutation in CYLD inactivates its enzyme function by structural perturbation and induces cell migration and proliferation.

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In addition, CYLD m induced an increased rate of cell migration as assessed by a scratch wounding assay, while CYLD WT markedly slowed cell migration (XREF_FIG).

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CYLD inhibits cell migration.

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CYLD inhibits cell migration. 2 / 2

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In addition, CYLD substantially slowed down scratchwounding induced cell migration (XREF_FIG).

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In addition, CYLD m induced an increased rate of cell migration as assessed by a scratch wounding assay, while CYLD WT markedly slowed cell migration (XREF_FIG).

21478324

CYLD affects RIPK2

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CYLD inhibits RIPK2.

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CYLD inhibits RIPK2. 4 / 4

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CYLD has been reported to inhibit RIPK2 induced signaling when overexpressed, but the function of endogenous CYLD in NOD2 signaling remains unexplored and its role as a DUB is unknown.

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Thus, the underlying infection determines the impact of RIPK2 and CYLD on the outcome of the disease and our identification of a direct inhibition of RIPK2 by CYLD provides a mechanistical explanation of the antagonistic effects of these two signaling molecules.

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CYLD Impairs RIPK2 Mediated Activation and Antibacterial Function of BMDM.

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CYLD activates RIPK2.

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CYLD activates RIPK2. 2 / 2

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To study whether CYLD directly regulates RIPK2 in Lm infected BMDM, we immunoprecipitated CYLD from Lm infected IFN-gamma-stimulated WT and Cyld -/- BMDM.

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Autophagy is an intrinsic defense mechanism against Lm and, therefore, we further investigated whether CYLD-dependent RIPK2 and ERK1/2 activation influences the formation of autophagosomes.

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CYLD affects CASP8

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CYLD activates CASP8.

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CYLD activates CASP8. 4 / 4

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CYLD was also found to promote the assembly of an alternative caspase-8 activating complex containing RIP1 and FADD [XREF_BIBR].

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Increased caspase-8 activation was also observed in selenite treated cells transfected with CYLD, indicating that CYLD promoted caspase-8 activation via RIP1 deubiquitination (XREF_FIG).

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An alternative explanation holds that CYLD is the target of caspase-8 during the decision point between apoptosis vs. necroptosis, although this model is not mutually exclusive from the aforementioned.

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These changes in sensitivity to TNF-alpha cytoxicity, mediated by the treatment of siCLIPR-59 or siCYLD, correlated with differences in RIP1 ubiquitination (XREF_SUPPLEMENTARY) These findings thus suggest that both CLIPR-59 and CYLD are essential for activation of Caspase-8 by TNF-alpha in the presence of Compound-3.

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CYLD inhibits CASP8.

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CYLD inhibits CASP8. 2 / 2

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Consistent with the data above, silencing CYLD largely abolished caspase 8 activation and necroptotic cell death induced by 5z-7 plus TNFalpha (XREF_FIG).

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24577083

LEF1 affects CYLD

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LEF1 inhibits CYLD.

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LEF1 inhibits CYLD. 3 / 3

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TNFa induced necrotic signaling can be blocked in some chronic leukemias by the action of LEF1 (Lymphoid Enhancer binding Factor 1), which acts on the Wnt and betaCatenin pathway to downregulate CYLD at the transcriptional level [XREF_BIBR].

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ERK inhibits CYLD. 3 / 3

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Moreover, we demonstrate that suppression of CYLD by ERK1/2 signaling plays an important role in maintaining RIP1 expression, and that melanoma cells with acquired resistance to BRAF inhibitors are more critically dependent on RIP1 for survival.

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Salicylate inhibits CYLD. 2 / 2

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Taken together, these findings indicated that CYLD negatively regulates the activation of TAK1, p38, and AP-1.

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By interacting with TRAF2, CYLD prevents p38MAPK activation.

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CYLD reduced activation of p65, JAK2, STAT3, and p38 MAPK as well as fibrin production in livers of Listeria infected WT mice.

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CYLD Impairs Production of Cytokines, ROS, and NO and Reduces Activation of NF-kappaB, ERK1/2, and p38MAPK in Lm Infected BMDM.

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Thus, CYLD prevents excessive activation of TAK1 and p38, which results in reduced FOXP3 expression and Treg generation.

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CYLD affects MAPK

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CYLD inhibits MAPK. 5 / 5

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Recently, we, along with others, have demonstrated that CYLD also inhibits MAPKs including p38 and JNK xref – xref .

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CYLD was shown to negatively regulate NF-kappaB and MAPK activation by removing ubiquitin chains from key signalling molecules including NEMO, TRAF2, TRAF6 and RIPK1.

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Moreover, knockdown of CYLD enhanced mitogen activated protein kinase (MAPK) ERK- and p38 mediated expression of c-jun, c-fos, and c-myc, which govern Nrf2 expression in cardiomyocytes.

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CYLD also negatively regulates the c-Jun N-terminal kinase (JNK) signaling pathway and mitogen activated protein kinase (MAPK) pathway, which are known to participate in a wide range of cellular processes, including proliferation, differentiation, and apoptosis of cholesteatoma [XREF_BIBR, XREF_BIBR].

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CREB1 affects CYLD

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CREB1 decreases the amount of CYLD. 5 / 5

5 |

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No evidence text available

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No evidence text available

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biopax:msigdb

No evidence text available

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biopax:msigdb

No evidence text available

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biopax:msigdb

No evidence text available

PDE4 affects CYLD

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PDE4 inhibits CYLD.

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PDE4 inhibits CYLD. 3 / 3

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CYLD inhibits cell adhesion. 3 / 3

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CYLD activates RELA.

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CYLD activates RELA. 1 / 1

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Thus, Romidepsin NF-kappaB p65 downregulation may be mediated, at least in part, by CYLD overexpression.

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CYLD affects NFKB1

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CYLD activates NFKB1.

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CYLD activates NFKB1. 3 / 3

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CYLD inhibits CTNNB1. 4 / 4

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In the Wnt signal transduction pathway, CYLD inhibits beta-catenin signaling by removing Lysine 63 linked ubiquitination from Dishevelled.

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Loss of CYLD in HMCLs was found to enhance beta-catenin stabilization and localization to the nucleus, increase beta-catenin-LEF and TCF reporter activity, and enhance MM cell growth and survival.

29776381

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In human cylindroma, CYLD negatively regulates Wnt and beta-catenin signaling via deubiquitination of Dishevelled, which is a key component in Wnt mediated beta-catenin nuclear translocation.

22235375

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reach

Increased CYLD expression may likewise diminish Wnt pathway activation and beta-catenin accumulation (XREF_FIG) via K63 linked deubiquitination of Dvl.

23034333

CYLD activates CTNNB1.

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CYLD activates CTNNB1. 1 / 1

| 1

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Loss of the tumor suppressor CYLD enhances Wnt and beta-catenin signaling through K63 linked ubiquitination of Dvl.

20227366

STAT3 affects CYLD

| 5

STAT3 activates CYLD.

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STAT3 activates CYLD. 3 / 3

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Importantly, STAT3 siRNA treatment induced 100% mortality of Lm infected Cyld -/- mice, thus, resembling WT mice (XREF_FIG).

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Accordingly, knockdown of STAT3 significantly reduced serum IL-6 levels in Lm infected Cyld -/- mice as compared to mock treated infected Cyld -/- mice as well as untreated infected Cyld -/- mice (XREF_FIG).

| 3

CYLD inhibits reactive oxygen species. 3 / 3

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CYLD Impairs Production of Cytokines, ROS, and NO and Reduces Activation of NF-kappaB, ERK1/2, and p38MAPK in Lm Infected BMDM.

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CYLD reduced IL-6, ROS production and killing of Lm in Listeria infected macrophages by impairing NF-kappaB activation.

| 3

CYLD-Y485A bound to ITCH inhibits cytokine production. 2 / 2

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CYLD inhibits cytokine production. 1 / 1

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Instead, CYLD limits extension of Lys63-Ub and Met1-Ub conjugated to RIPK2 to restrict signaling and cytokine production.

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CYLD activates cytokine production.

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CYLD activates cytokine production. 2 / 2

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CYLD Augments Cytokine Production in the Brain of PbA Infected Mice.

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CYLD affects SMAD7

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CYLD activates SMAD7.

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CYLD activates SMAD7. 3 / 3

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The study performed in CYLD-knockout mice reported that CYLD targets SMAD7 protein for deubiquitylation and inhibits TGF-beta signalling in the development of regulatory T cells.

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The Deubiquitinase CYLD Targets Smad7 Protein to Regulate Transforming Growth Factor beta (TGF-beta) Signaling and the Development of Regulatory T Cells *.

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CYLD inhibits NFKBIA. 2 / 2

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Treatment with BAY 11-7085, a known NF-kappaB antagonist that blocks IkappaBalpha phosphorylation and NF-kappaB transactivation, effectively abrogated the CYLD siRNA induced IkappaBalpha degradation.

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While the CYLD deficiency slightly decreased the basal expression levels of IkappaBalpha and IkappaBbeta proteins, it did not affect the basal expression of IkappaBepsilon in RASMCs (XREF_FIG).

22406061

CYLD activates NFKBIA.

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CYLD-C601A activates NFKBIA. 1 / 1

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Consistent with our previous study [XREF_BIBR], the inhibitory function of CYLD on NF-kappaB relies on its intact catalytic activity because expression of a catalytically inactive CYLD C601A mutant, in which cysteine601 is substituted by alanine, could not enhance the abundance of IkappaBalpha to the equivalent extent as wild-type CYLD did (XREF_SUPPLEMENTARY).

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CYLD activates NFKBIA. 1 / 1

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CYLD decreases the amount of NFKBIA.

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Modified CYLD decreases the amount of NFKBIA. 1 / 1

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In this study, high glucose inhibited expression of IkappaBalpha was significantly reversed by the overexpression of CYLD, and p-IkappaBalpha, NF-kappaBp65, and p-NF-kappaBp65 proteins levels were significantly decreased.

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Hsa-miR-362-5p affects CYLD

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Hsa-miR-362-5p decreases the amount of CYLD. 4 / 4

4 |

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No evidence text available

25449782

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No evidence text available

25909817

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No evidence text available

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No evidence text available

24495516

Cyclin affects CYLD

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Cyclin activates CYLD. 4 / 4

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Importantly, the increased cyclin D1 promoter activity in Cyld -/- keratinocytes was normalized after re-expression of Cyld and completely abolished in the absence of a functional NF-kappaB binding si[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Interestingly, TPA also triggered the recruitment of p50 or p52, but not p65, to the cyclin D1 promoter in Cyld -/- keratinocytes.

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TNF-alpha treatment failed to activate the cyclin D1 promoter in Cyld +/+ as well as Cyld -/- keratinocytes, consistent with the inability of TNF-alpha to stimulate keratinocyte proliferation.

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The increased cyclin D1 activation in Cyld -/- keratinocytes was normalized upon reintroduction of the Cyld protein.

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CYLD affects bsk

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CYLD inhibits bsk. 4 / 4

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beta1-integrin and pJNK are downregulated by CYLD and display crosstalk.

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At the molecular level, CYLD decreased beta1-integrin and inhibited pJNK induction by tumor necrosis factor-alpha or cell attachment to collagen IV.

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At the molecular level, CYLD decreased beta1-integrin and inhibited pJNK induction by TNFalpha or cell-attachment to collagen IV.

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Further in line with these data, CYLD inhibited pJNK induction not only by TNFalpha but also by cell adhesion to collagen IV, a natural substrate and activator of beta1-integrin (XREF_FIG).

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CYLD affects Tax

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CYLD inhibits Tax. 4 / 4

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Importantly, expression of wildtype CYLD, but not its catalytically inactive mutant, strongly inhibited Tax stimulated activation of IKK, supporting a role for Tax ubiquitination in the activation of IKK signaling.

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CYLD inhibits Tax stimulated IKK activation via deubiquitinating Tax, although the CYLD mediated Tax deubiquitination does not affect Tax activation of Tak1.

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CYLD inhibits Tax stimulated activation of IKK but not that of Tak1.

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These findings suggest that CYLD negatively regulates the signaling function of Tax through inhibition of Tax ubiquitination.

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CYLD affects Multiple Myeloma

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CYLD inhibits Multiple Myeloma. 4 / 4

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Altogether, our findings identify CYLD as a negative regulator of NF-kappaB and Wnt and beta-catenin signaling in MM and indicate that loss of CYLD enhances MM aggressiveness through Wnt pathway activation.

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Functional assays revealed that CYLD represses MM cell proliferation and survival.

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Loss of the deubiquitinating enzyme CYLD has been shown to enhance MM aggressiveness via Wnt pathway activation [XREF_BIBR].

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Loss of CYLD in HMCLs was found to enhance beta-catenin stabilization and localization to the nucleus, increase beta-catenin-LEF and TCF reporter activity, and enhance MM cell growth and survival.

29776381

CYLD affects GS26575

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CYLD inhibits GS26575. 4 / 4

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CYLD, another DUB, is reported to limit NF-kappaB activation by removing K63- and M1 linked poly-ubiquitin chains on several complex I components (including TRAF2, NEMO and RIPK1), thereby disrupting the ubiquitin scaffold required for the recruitment and activation of the TAB2/3-TAK 1 and NEMO-IKKalpha-IKKbeta complexes [XREF_BIBR, XREF_BIBR - XREF_BIBR].

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Once recruited, CYLD limits NF-kappaB activation by removing K63 linked and M1 linked poly-Ub chains on several components of complex I, including RIPK1 [XREF_BIBR, XREF_BIBR - XREF_BIBR].

27066894

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Proteasome inhibits CYLD. 3 / 3

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HeLa and SiHa cells were exposed to MG132 (10 microM) for one hour prior to harvesting protein in order to prevent E6 mediated, proteasome dependent degradation of CYLD.

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CYLD may be functionally inactivated through its phosphorylation, degraded by the ubiquitination and proteasome pathway, or repressed at the level of transcription.

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The HPV encoded oncogenic protein E6 promotes hypoxia induced NF-kappaB activation by triggering the ubiquitination and proteasome mediated degradation of CYLD [XREF_BIBR].

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Proteasome increases the amount of CYLD.

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Proteasome increases the amount of CYLD. 1 / 1

IKK_complex inhibits CYLD. 3 / 3

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Reiley et al have shown that NEMO is required for the IKK complex to phosphorylate and inhibit the deubiquitinase CYLD [ xref ], a critical component of the necrotic machinery [ xref ], as can the TNF-inducible IKKε [ xref ].

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On the contrary, ectopic expression of IKK significantly reduced CYLD protein abundance in 293T cells ectopically expressing HA tagged CYLD.

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IKK blockade reactivates CYLD, as evidenced by the reduction in RIPK1 ubiquitination, which leads to the association of RIPK1 with the death inducing signaling complex (DISC) to trigger cell death.

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IKK_complex activates CYLD.

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IKK_complex activates CYLD. 1 / 1

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IKK mediated CYLD activation is expected to remove K63 linked polyubiquitins from PSD proteins and thus regulate their trafficking.

24928390

HDAC6 affects CYLD

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HDAC6 activates CYLD.

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HDAC6 activates CYLD. 3 / 3

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However, TSA treatment or HDAC6 depletion alone did not induce interaction of CYLD with Bcl-3 (XREF_FIG).

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This is supported by the finding that depletion of HDAC6 was not sufficient to induce the interaction of CYLD with Bcl-3, but TPA mediated activation of CYLD is additionally required.

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In addition, modulation of HDAC6 activity or localization has been shown to mediate the actions of CYLD, Dio3, Plk1, and ribosylation factor like proteins in ciliogenesis XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.

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HDAC6 inhibits CYLD.

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HDAC6 inhibits CYLD. 1 / 1

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Small-molecule inhibitors of HDAC6 could partially rescue the ciliary defects in CYLD knockout mice.

25342559

CYLD affects homeostatic process

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CYLD inhibits homeostatic process.

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CYLD inhibits homeostatic process. 3 / 3

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These findings suggest that CYLD can both positively and negatively regulate signal transduction and homeostasis of B cells in vivo, depending on the expression of CYLD splice variants.

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At a genomic level, we established that neither TRKB and TRKC amplification, nor that of BDNF and NT3/4 was demonstrated to account for the overexpression seen in cylindroma tumours, suggesting that CYLD dysfunction perturbs normal TRK homeostasis.

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CYLD activates homeostatic process.

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CYLD activates homeostatic process. 1 / 1

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CYLD contributes to hepatic homeostasis and restoration upon liver injury.

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CYLD affects cell growth

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CYLD inhibits cell growth.

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CYLD inhibits cell growth. 3 / 3

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Exogenous expression of CYLD inhibited melanoma cell growth and migration in vitro.

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CYLD activates STAT1. 2 / 2

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This indirect regulation of STAT1 signaling by CYLD resembles the function of the deubiquitinating enzyme A20, which also inhibits STAT1 activation indirectly by suppressing NF-kappaB activation.

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In accordance with the CYLD independent activation of STAT1 by IFN-gamma, we could not detect a direct interaction of CYLD with STAT1.

26834734

SRF affects CYLD

| 4

SRF decreases the amount of CYLD.

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SRF decreases the amount of CYLD. 2 / 2

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Knockdown of SRF by siRNA significantly reduced levels of CYLD, indicating that CYLD expression is regulated by SRF.

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NIBAN2 decreases the amount of CYLD. 2 / 2

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The combined results identified that MEG3 suppressed melanoma cell proliferation and invasion by regulating the expression of CYLD mediated by sponging miR-499-5p.

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Overexpression of MEG3 dramatically decreased the level of miR-499-5p and promoted CYLD protein expression; however, downregulation of MEG3 distinctly increased the miR-499-5p expression and inhibited CYLD protein expression.

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Modified NIBAN2 decreases the amount of CYLD. 1 / 1

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NIBAN2 increases the amount of CYLD.

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Modified NIBAN2 increases the amount of CYLD. 1 / 1

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29808164

IL6 affects CYLD

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IL6 activates CYLD.

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IL6 activates CYLD. 2 / 2

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BCL3 decreases the amount of CYLD. 2 / 2

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In light of our current findings, it will be important to determine whether the increased nuclear Bcl-3 levels in these tumor cell lines are (like in cylindromas and epidermal tumors) also caused by a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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These data prompted us to investigate the role of LEF1 in selenite triggered CYLD upregulation.

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Collectively, our findings demonstrate that selenite caused CYLD upregulation via LEF1 and cIAP downregulation, both of which contribute to the degradation of ubiquitin chains on RIP1 and subsequent caspase-8 activation and apoptosis.

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We found that selenite triggered cIAP degradation, and CYLD upregulation via the transcription factor lymphoid enhancer factor-1 (LEF1).

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TNFSF11 affects CYLD

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TNFSF11 increases the amount of CYLD. 3 / 3

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40 RANKL stimulated osteoclastogenesis potently induces the expression of CYLD, and the accumulated CYLD targets TRAF6 by interacting with the adaptor protein, p62.

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32 In mouse bone marrow derived macrophages, CYLD expression is strongly induced by RANKL, but not by TNF-alpha or LPS.

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Furthermore, MG132 treatment extended the half-life of endogenous CYLD protein following RANKL stimulation in RAW264.7 mouse macrophage cells, as RANKL stimulation induces CYLD mRNA expression, thereby bypassing the down-regulation of CYLD mRNA expression by MG132.

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TLR4 affects CYLD

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TLR4 activates CYLD. 3 / 3

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Cleavage of CYLD induced by TLR4 stimulation was not affected in the Myd88 -/- BMDMs (XREF_FIG), but was abrogated in the Trif -/- BMDMs (XREF_FIG), indicating that CASPASE-8 activation was dependent on TRIF.

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The LPS induced TLR-4 ligation recruits FADD and caspase-8 in a complex and initiates the cleavage of CYLD.

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The LPS induced TLR-4 ligation recruits FADD and caspase-8 in a complex and initiates the cleavage of CYLD (Legarda et al., 2016) .

| DOI

TCF3 affects CYLD

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TCF3 decreases the amount of CYLD. 3 / 3

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biopax:msigdb

No evidence text available

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biopax:msigdb

No evidence text available

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biopax:msigdb

No evidence text available

MIB2 affects CYLD

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MIB2 inhibits CYLD. 3 / 3

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Here, using the cell-free based AlphaScreen and pulldown assays to detect protein protein interactions, along with immunofluorescence assays and murine Mib2-knockout cells and animals, we demonstrate that MIB2 promotes proteasomal degradation of CYLD and enhances NF-kappaB signaling.

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The E3 ubiquitin ligase MIB2 enhances inflammation by degrading the deubiquitinating enzyme CYLD.

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Together, these results suggest that MIB2 enhances NF-kappaB signaling in inflammation by promoting the ubiquitin dependent degradation of CYLD.

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KITLG affects CYLD

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KITLG inhibits CYLD. 3 / 3

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Altogether, these results support the model that CYLD degradation by SCF beta-TRCP plays a critical role in governing the timely activation of the NF-kappaB signaling pathway to control the osteoclast differentiation process (XREF_SUPPLEMENTARY).

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Taken together, these results indicated that SCF beta-TRCP might negatively regulate the protein stability of CYLD.

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CYLD affects sub

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CYLD inhibits sub. 3 / 3

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Similarly, CYLD Ser418 phosphorylation upon co-expression of IKKepsilon was found to decrease its DUB activity.

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Interestingly, phosphorylation of CYLD has been shown to inhibit its DUB activity XREF_BIBR - XREF_BIBR.

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We also checked in both lines of transgenic mice, that, as expected, the CYLD C/S mutant was catalytically inactive and inhibited the DUB function of the endogenous CYLD, as we previously described that occurred in the epidermal HaCaT-CYLD C/S and PDVC57-CYLD C/S cells [XREF_BIBR, XREF_BIBR] (XREF_SUPPLEMENTARY).

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CYLD affects TLR4

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CYLD inhibits TLR4. 3 / 3

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However, the specific CYLD target modulating TLR3 and TLR4 responses remains to be determined XREF_BIBR (Sidebar A).

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TLR4 engagement in the presence of zVAD-fmk did not lead to MLKL oligomerization in CYLD deficient cells (XREF_FIG), demonstrating that removal of CYLD prevents TLR4 from inducing necroptosis.

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CYLD also negatively regulates NF-kappaB activation in IL-1R and TLR4 signaling through its DUB activity (Sun, 2010b).

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CYLD affects RAC1

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CYLD activates RAC1. 3 / 3

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Our findings provide new insight into the role of CYLD induced RAC1 activation in melanoma cell migration.

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Our findings provide new insight into the role of CYLD-induced RAC1 activation in melanoma cell migration.

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Our findings provide new insight into the role of CYLD-induced RAC1 activation in melanoma cell migration.

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CYLD affects PSMD4

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CYLD activates PSMD4. 3 / 3

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The silencing of CYLD significantly inhibited AF transdifferentiation and activation as evidenced by the expression of contractile proteins, the production of the proinflammatory cytokines MCP-1 (monocyte chemotactic protein 1) and IL-6 (interleukin-6), the deposition of extracellular matrix, and cell migration.

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We further asked whether CYLD mediates AF activation via the regulation of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) as it is an essential factor during AF transdifferentiation.

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Indeed, the silencing of CYLD repressed transforming growth factor-β1-induced and homocysteine-induced Nox4 upregulation and reactive oxygen species production, whereas Nox4 overexpression greatly rescued the inhibitory effect on AF activation by CYLD silencing.

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CYLD affects LCK

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CYLD activates LCK. 3 / 3

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Specifically, CYLD positively regulates LCK in thymocytes and negatively regulates TAK1 in peripheral T cells XREF_BIBR, XREF_BIBR.

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We have previously shown that CYLD positively regulates LCK function and TCR proximal signaling in thymocytes.

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In contrast to its negative role in the regulation of NF-kappaB, CYLD positively regulates LCK 18, a SRC family protein tyrosine kinase that is required for TCR proximal signalling and thymocyte development 77.

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CAMK2B affects CYLD

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CAMK2B activates CYLD. 3 / 3

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Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity.

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Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity.

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Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity.

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ATF3 affects CYLD

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ATF3 decreases the amount of CYLD. 3 / 3

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biopax:msigdb

No evidence text available

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biopax:msigdb

No evidence text available

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biopax:msigdb

No evidence text available

Pirinixic acid affects CYLD

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Pirinixic acid decreases the amount of CYLD.

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Pirinixic acid decreases the amount of CYLD. 2 / 2

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SMARCE1 activates CYLD. 2 / 2

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JNK activates CYLD. 2 / 2

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EFEMP1 inhibits CYLD. 2 / 2

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CYLD inhibits TLR2. 2 / 2

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For example, CYLD has been proven to negatively regulate TLR2 by TRAF6 and TRAF7 and an antiviral response in an H. influenza co-infection model [XREF_BIBR, XREF_BIBR].

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The ubiquitin editing enzyme CYLD inhibits TRAF6 and -7 and TLR2 [XREF_BIBR].

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CYLD activates TLR2.

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CYLD activates TLR2. 1 / 1

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Another interesting finding in this study is the experimental evidence for the negative regulation of S. pneumoniae induced TLR2 up-regulation by tumor suppressor CYLD.

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CYLD affects RIPK3

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CYLD activates RIPK3.

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CYLD activates RIPK3. 2 / 2

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Then, we found that RIP3 accounts for shikonin induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3.

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CYLD inhibits RIPK3.

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CYLD inhibits RIPK3. 1 / 1

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Then, we found that RIP3 accounts for shikonin induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3.

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CYLD affects MAPK8

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CYLD inhibits MAPK8.

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CYLD inhibits MAPK8. 2 / 2

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The increased proliferation was thought to be mediated by MAPK8 signalling, which is negatively regulated by CYLD.

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CYLD activates MAPK8.

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CYLD activates MAPK8. 1 / 1

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Taken together, it is evident that PDE4B negatively regulates CYLD expression and mediates NTHi induced inflammation via specific activation of JNK2 but not JNK1 pathway.

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CYLD affects Fibroblasts

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CYLD inhibits Fibroblasts.

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CYLD inhibits Fibroblasts. 2 / 2

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CYLD activates E3_Ub_ligase. 2 / 2

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CYLD inhibits E3_Ub_ligase.

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CYLD inhibits E3_Ub_ligase. 1 / 1

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CYLD affects Death

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CYLD activates Death.

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CYLD activates Death. 2 / 2

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biopax:msigdb

No evidence text available

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biopax:msigdb

No evidence text available

MAPK affects CYLD

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MAPK increases the amount of CYLD. 2 / 2

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ctd

No evidence text available

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Vorinostat activates CYLD.

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Vorinostat activates CYLD. 1 / 1

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Roflumilast inhibits CYLD. 1 / 1

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We have already demonstrated that specific PDE4 inhibitors, Rolipram and Roflumilast, when preadministered systemically, upregulated CYLD and suppressed subsequent inflammation in the mouse models of middle ear inflammation (OM) and lung inflammation (XREF_FIG and XREF_FIG).

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Roflumilast activates CYLD.

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Roflumilast activates CYLD. 1 / 1

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Phosphatidic acid increases the amount of CYLD. 1 / 1

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Interestingly, our data also unveiled that PA triggers the expression of CYLD, whereas the molecular mechanisms involved have not been clarified so far.

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Phosphatidic acid activates CYLD.

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Phosphatidic acid activates CYLD. 1 / 1

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Cycloheximide inhibits CYLD. 1 / 1

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Cycloheximide did not block CYLD cleavage and degradation, whereas it efficiently blocked the re-synthesis of IkappaBalpha following LPS stimulation (XREF_SUPPLEMENTARY).

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Cycloheximide activates CYLD.

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Cycloheximide activates CYLD. 1 / 1

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Benzo[a]pyrene increases the amount of CYLD. 1 / 1

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ctd

No evidence text available

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Benzo[a]pyrene decreases the amount of CYLD.

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Benzo[a]pyrene decreases the amount of CYLD. 1 / 1

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TRIP6 inhibits CYLD. 1 / 1

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TRIP6 also attenuates the association of CYLD with TRAF6 in unstimulated HEK293T cells, although the effect is much weaker.

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TRIP6 activates CYLD.

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TRIP6 activates CYLD. 1 / 1

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Nonetheless, depletion of TRIP6 can significantly enhance the association of A20 or CYLD with TRAF6 in ovarian cancer cells and promote the binding of A20 to TRAF6 in glioblastoma cells, suggesting that targeting TRIP6 may prove to be an effective strategy to restore the function of A20 and CYLD in restricting the NF-kappaB activity in these cancer cells.

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TRAF6 affects CYLD

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TRAF6 inhibits CYLD.

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TRAF6 inhibits CYLD. 1 / 1

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TRAF6 activates CYLD.

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TRAF6 activates CYLD. 1 / 1

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SNAIL increases the amount of CYLD. 1 / 1

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The transcriptional repressor SNAIL regulates E-cadherin and represses the expression of the deubiquitinating enzyme CYLD.

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SNAIL decreases the amount of CYLD.

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SNAIL decreases the amount of CYLD. 1 / 1

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N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal decreases the amount of CYLD. 1 / 1

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N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal activates CYLD.

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N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal activates CYLD. 1 / 1

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CYLD inhibits proteolysis. 1 / 1

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In agreement with this finding, CYLD m did not induce protein degradation, instead resulted in an elevation of c-Fos and c-Jun in response to cell starvation and subsequent treatment with EGF (XREF_SUPPLEMENTARY).

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CYLD activates proteolysis.

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CYLD activates proteolysis. 1 / 1

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CYLD inhibits autophagy. 1 / 1

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Noteworthy, CYLD also inhibited autophagy of Listeria in a RIPK2-ERK1/2-dependent manner.

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CYLD activates autophagy.

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CYLD activates autophagy. 1 / 1

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CYLD inhibits TCR. 1 / 1

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Because ERK is not affected by the Cyld deficiency, it is unlikely that CYLD negatively regulates a further upstream component in the TCR signaling pathway.

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CYLD activates TCR.

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CYLD activates TCR. 1 / 1

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CYLD inhibits Notch. 1 / 1

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Consistent with these results, we found that ectopic expression of CYLD is sufficient to block Notch induced activation of an NFkappaB dependent reporter in HEK-293T (XREF_SUPPLEMENTARY).

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CYLD activates Notch.

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CYLD activates Notch. 1 / 1

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CYLD inhibits MALT1. 1 / 1

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CYLD increases the amount of IFNG. 1 / 1

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Indeed, CYLD siRNA reversed the decrease in perforin, granzyme B, IFN-gamma and CD107a expression (XREF_FIG).

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CYLD activates IFNG.

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CYLD activates IFNG. 1 / 1

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CYLD increases the amount of CYCD1-1. 1 / 1

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We have reported earlier that CYLD decreases the proliferation of keratinocytes and melanoma cells by retaining Bcl-3 in the cytoplasm and thereby reducing the expression of cyclin-D1.

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CYLD decreases the amount of CYCD1-1.

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CYLD decreases the amount of CYCD1-1. 1 / 1

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biopax:msigdb

No evidence text available

VSX1 affects CYLD

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No evidence text available

SP1 affects CYLD

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SP1 decreases the amount of CYLD. 1 / 1

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biopax:msigdb

No evidence text available

SH3-like domain affects CYLD

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SH3-like domain activates CYLD. 1 / 1

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The possession of both proline rich motifs and an SH3 like domain could allow CYLD to interact with target proteins containing either SH3 domains or proline rich motifs.

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SERPINE1 affects CYLD

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biopax:msigdb

No evidence text available

RHOA affects CYLD

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RHOA activates CYLD. 1 / 1

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In addition, we find that RhoA mediated cytoskeletal rearrangement, chromosome separation, and cell polarization are altered in CYLD depleted cells.

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REL affects CYLD

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REL decreases the amount of CYLD. 1 / 1

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biopax:msigdb

No evidence text available

RBCK1 affects CYLD

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RBCK1 inhibits CYLD. 1 / 1

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Possibly, HOIL-1 or another factor with Met1-Ub-binding capacity would prevent CYLD from gaining access to and cleaving the Met1-Ub on HOIP, whereas OTULIN would have access via its higher affinity toward Met1-Ub.

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RAF1 affects CYLD

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RAF1 decreases the amount of CYLD. 1 / 1

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RAB11FIP5 affects CYLD

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biopax:msigdb

No evidence text available

PCSK7 affects CYLD

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PCSK7 inhibits CYLD. 1 / 1

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We studied mice with liver parenchymal cell (LPC)-specific disruption of the CYLD lysine 63 deubiquitinase gene (Cyld), with or without disruption of Relb (Cyld DeltaLPC mice and Cyld and Relb DeltaLPC mice) and compared them to C57BL/6 mice (controls).

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PCI 5002 affects CYLD

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PCI 5002 increases the amount of CYLD. 1 / 1

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No evidence text available

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NR3C1 affects CYLD

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Then, we found that RIP3 accounts for shikonin induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3.

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MEIS1 affects CYLD

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To examine how CYLD affects epidermal homeostasis and tumorigenesis, we generated transgenic mice with keratin 14 promoter driven expression of a human CYLD mutant-932 (CYLD m) which lacks the 21 amino acid residues at the C-terminal end (XREF_SUPPLEMENTARY).

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JUN affects CYLD

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We next demonstrated that Ga strongly up-regulated the expression of Traf6, p62 and Cyld genes, and we observed concomitantly an inhibition of IkappaB degradation and a blockade of NFkappaB nuclear translocation, which regulates the initial induction of Nfatc1 gene expression.

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FSH affects CYLD

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FSH activates CYLD. 1 / 1

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In detail, both SPATA2 and CYLD were induced by TNF-alpha and IL-1beta (but not FSH) after 3hours.

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FADD affects CYLD

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FADD activates CYLD. 1 / 1

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CYLD affects ST13

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CYLD activates ST13. 1 / 1

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CYLD affects SRF

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CYLD activates SRF. 1 / 1

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More importantly, SB203580 decreased CYLD protein levels by inhibiting SRF phosphorylation and indirectly prevented SRF from binding to a CYLD promoter.

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CYLD affects SQSTM1

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CYLD affects RPS15

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CYLD inhibits RPS15. 1 / 1

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USP3, USP21 and CYLD inhibit RIG‐I K63‐linked ubiquitination and activation.

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CYLD affects RLR

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CYLD inhibits RLR. 1 / 1

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CYLD affects MFT1

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CYLD activates MFT1. 1 / 1

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In 1996, the gene locus for BSS was mapped to 16q12-13, and, in 2000, mutations in the cylindromatosis (CYLD) gene were determined to cause BSS, familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma type 1 (MFT1; OMIM 601606).

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CYLD affects MCP-1

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We next determined whether cAMP dependent PKA pathway also has a critical role in mediating NTHi induced CYLD expression and inflammation.

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